Ginkgo biloba special extract EGb 761® in generalized anxiety disorder and adjustment disorder with anxious mood: A randomized, double-blind, placebo-controlled trial
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 population (Ansseau et al., 2004), and a lifetime prevalence of 4–7% in the general population (Allgulander et al., 2003). From a survey in 88 outpatients of an internal medicine clinic Sansone et al. (2004) reported a 33% prevalence of generalized anxiety symptoms. Among the anxiety disorders classified by the diagnostic and statistical manual of mental disorders, third edition – revised (DSM-III-R, American Psychiatric Association, 1987) GAD is the second most frequent diagnosis found (Lépine and Lellouch, 1994).
Another disorder associated with symptoms of anxiety which are generalized rather than phobic in nature is adjustment disorder with anxious mood (ADWAM). Its prevalence was 7.8% as a sole diagnosis and a further 4.2% as comorbidity with other axis I and II diagnoses in a consultation-liaison psychiatry setting (Strain et al., 1998). In a primary care setting, the prevalence of ADWAM was 1% in the whole population of consecutive patients, 4.5% among the patients with psychological complaints and a further 9.2% in association with other psychiatric disorders (Semaan et al., 2001).
GAD is amenable to psychotherapy (primarily cognitive-behavioral therapy) as well as pharmacotherapy. Current recommendations include benzodiazepines, buspirone and antidepressants, above all serotonin and noradrenalin reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs) (Allgulander et al., 2003). Benzodiazepines have the advantage of quick symptom relief, but side effects (sedation, psychomotor and cognitive impairment), physical dependence and withdrawal effects limit their long-term use. Buspirone is effective in the short-term treatment of GAD, but long-term studies are missing. All types of drugs currently recommended for treating GAD may adversely affect patients’ functioning at work, car-driving and social life. Symptoms of anxiety, although often at a sub-syndromal level, are frequently found in subjects suffering cognitive decline (Lyketsos et al., 2002, Chan et al., 2003, Forsell et al., 2003). In such cases, anxiety may be a symptom of the underlying disease itself or a reaction to the perception of mental decline.
There appears to be a gap between the frequency of ADWAM and high-grade evidence for the effectiveness of treatments. In a cross-sectional study of a sample of ADWAM patients drawn from general practitioners in France (Semaan et al., 2001), 74% were prescribed drug treatments and 90% received non-pharmacological treatments. Anxiolytics were prescribed most frequently (60%), followed by antidepressants (11%) and hypnotics (8%). A Dutch group of experts issued a discussion paper suggesting practice guidelines based on “existing evidence, experience in adjacent fields and consensus procedures” (van der Klink and van Dijk, 2003) for the treatment of work-related adjustment disorders. While existing evidence was sparse, their proposed three-phase psychotherapeutic approach was based mainly on experience and consensus.
Ginkgo biloba special extract EGb 761® is registered in Germany and many other countries for the treatment of dementia disorders. In two large trials the drug has been shown to improve cognitive performance, activities of daily living and social functioning as well as the overall condition of patients with dementia (Kanowski et al., 1996, Le Bars et al., 1997). The efficacy of EGb 761® in the treatment of dementia and aging-related cognitive impairment has also been demonstrated in further studies, reviewed by Oken et al. (1998) and Birks et al. (2002). Cognition-enhancing effects in mentally healthy elderly subjects have been reported recently by Mix and Crews (2002) and Cieza et al. (2003). In one of the early studies enrolling patients with cognitive impairment due to cerebrovascular disease, anxiety was one of the non-cognitive symptoms relieved significantly by EGb 761® treatment (Eckmann and Schlag, 1982). Beneficial effects 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 efficacy 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® significantly reduced the detrimental effects 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 significantly 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 effects were demonstrated for anxiolytic drugs, such as diazepam and buspirone (Nöldner 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 significantly attenuated by the same extract fraction (Nöldner 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 effects of auditory perturbation and rises in plasma hormones were suppressed by EGb 761®. The drug effects 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 significantly less so in EGb 761®-treated animals. These findings suggest that EGb 761® interferes with the regulation of the activity of the hypothalamic–pituitary–adrenocortical (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® significantly attenuated the stress-induced rise in systolic and diastolic blood pressure without affecting the heart rate. A stress-related increase in salivary cortisol levels was observed in placebo-treated male subjects in the afternoon. This effect was absent in volunteers treated with EGb 761®. In a pilot study with a similarly standardized Ginkgo extract, the sleep pattern of depressed inpatients receiving trimipramine monotherapy was examined (Hemmeter et al., 2001). Under adjuvant Ginkgo treatment slow-wave sleep was enhanced, REM-density was decreased in sleep stage 1 and was increased in sleep stage 2. Sleep efficiency was improved and awakenings were reduced during Ginkgo intake. Most effects were lost after discontinuation of adjuvant Ginkgo treatment. The authors concluded that the improved sleep pattern was secondary to a weakening of tonic CRF-activity.
The objective of the present study was to establish whether the stress-alleviating and anxiolytic-like effects found in animal and volunteer studies translate into clinically meaningful anxiolytic effects in patients suffering from specified non-psychotic and non-phobic types of anxiety.
Section snippets
Patients and methods
The study was conducted in accordance with the current versions of the Declaration of Helsinki and the Good Clinical Practice guidelines. The protocol was reviewed by the independent ethics committees of the Chamber of Physicians of Baden-Württemberg and the Faculty of Medicine of the University Erlangen-Nuremberg. Informed consent was obtained from all patients after the nature of the study and the procedures to be followed had been fully explained and before any study-related procedures
Patient disposition and characteristics
Rapid enrollment of patients at 16 sites resulted in a slight over-recruitment with a total sample of 109 patients. 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
Discussion
In this study, we enrolled patients who fulfilled either the diagnostic criteria for generalized anxiety disorder (GAD) or those for adjustment disorder with anxious mood (ADWAM). Irrespective of the inclusion diagnosis, distinct improvements compared to placebo were seen in the clinicians’ structured rating, the HAMA, a standard measure of the severity of anxiety. The findings are corroborated by the patients’ structured self-ratings, EAAS and B-L′ as well as by the patients’ and physicians’
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