Ginkgo for elderly people with dementia and age-associated memory impairment: a randomized clinical trial

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Abstract

Preparations based on special extracts of the Ginkgo biloba tree are popular in various European countries. Previous studies have suggested the clinical efficacy of Ginkgo in patients with dementia, cerebral insufficiency, or related cognitive decline. However, most of these studies did not fulfill the current methodologic requirements. We assessed the efficacy of the G. biloba special extract EGb 761 in patients with dementia and age-associated memory impairment in relation to dose and duration of treatment. Our study was a 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Study participants were elderly patients with dementia (Alzheimer disease or vascular dementia) or age-associated memory impairment (AAMI). A total of 214 participants, recruited from 39 homes for the elderly in the Netherlands, were randomly allocated to Ginkgo (either 240 mg/d or 160 mg/d) or placebo (0 mg/d). After 12 weeks, the subjects in the two Ginkgo groups were randomized to continued Ginkgo treatment or placebo treatment. Primary outcome measures in this study were the Syndrome Kurz Test (SKT; psychometric functioning), the Clinical Global Impression of change (CGI-2; psychopathology, assessed by nursing staff), and the Nuremberg Gerontopsychological Rating Scale for Activities of Daily Living (NAI-NAA; behavioral functioning). One hundred twenty-three patients received Ginkgo (n = 79, 240 and 160 mg/d combined) or placebo (n = 44) during the 24-week intervention period. We found no statistically significant differences in mean change of scores between Ginkgo and placebo. The differences were SKT: +0.4 (90% confidence interval [CI] −0.9–1.7); CGI-2: +0.1 (90% CI −0.3–0.4), and NAI-NAA: −0.4 (90% CI −1.9–1.2). A positive difference is in favor of Ginkgo. Neither the dementia subgroup (n = 36) nor the AAMI subgroup (n = 87) experienced a significant effect of Ginkgo treatment. There was no dose-effect relationship and no effect of prolonged Ginkgo treatment. The trial results do not support the view that Ginkgo is beneficial for patients with dementia or age-associated memory impairment.

Introduction

Efforts to identify substances that stand out for their efficacy and safety in treating dementia and related cognitive disorders have yielded disappointing results until now. Several years ago, the Lancet published a criteria-based systematic review that showed a consistent beneficial effect of Ginkgo for patients with cerebral insufficiency [1]. Forty randomized controlled trials were included in that review, 39 of which showed a statistically significant effect or at least a positive trend for Ginkgo. However, the methodologic quality of many trials was considered to be poor. Moreover, the studies entailed a heterogeneous collection of target health problems, ranging from overt dementia to noncognitive manifestations of brain dysfunction, such as vertigo and tinnitus. More recently, the results of several new Ginkgo trials have been published. Most of them focused on dementia, were rather well designed, and showed positive effects of Ginkgo. Probably the most talked about is the trial of the North American EGb Study Group, which was published in the JAMA in 1997 and showed a modest improvement of the cognitive performance and the social functioning of the demented patients involved [2].

Medicinal ginkgo preparations are obtained through extraction of dried leaves of the Ginkgo biloba tree. G. biloba special extracts, such as EGb 761 and LI 1370, have been subjected to a standardized process of enrichment and purification, yielding fixed concentrations of two active substance classes (ginkgoflavone glycosides, 16% to 25%; terpene trilactones, usually 6%). These extracts have been registered as drugs for various indications in several European countries. Ginkgo is marketed in these countries under various brand names and has become a commercial best seller. Ginkgo monopreparations and multipreparations with Ginkgo constituents have also attracted a growing popularity as over-the-counter drugs [3], [4]. Several mechanisms of action have been described to explain the claimed nootropic properties of Ginkgo: increased tolerance to hypoxia; prevention of membrane damage through free radical scavenger activity; improvement of blood rheology and vasoregulating capacity, resulting in increased blood flow; prevention of post-traumatic or toxin-induced brain edema; platelet activating factor inhibition; and neuroprotective action by direct or by indirect (modulated through blood flow) influences on the nervous system [5].

We initiated a trial to retest the hypothesis that Ginkgo is beneficial to elderly people with dementia or age-associated memory impairment. The promising results of previous trials justified the inclusion of two additional research questions, one dealing with the dose dependency and the other with the durability of any ginkgo effect.

Section snippets

Study design

The trial was designed as a multicenter, randomized, placebo-controlled, double-blind trial (Figure 1). The eligible subjects were randomly allocated to one of three treatments: EGb 761 240 mg/d (“high dose”), 160 mg/d (“usual dose”), or 0 mg/d (placebo). This allowed us to study the dose-effect relationship in addition to the efficacy of Ginkgo. Participants who completed the first 12-week treatment period under Ginkgo were randomly allocated for a second 12-week treatment period to continue

Results

A total of 39 old peoples' homes participated in the trial. These homes housed 4459 residents, 781 (18%) of whom were preselected by the nursing staff for presumed cognitive problems. We excluded 268 persons at an early stage of the patient selection procedure mainly because of comorbidity, co-medication, and refusal by the patient; 513 (12%) proceeded to the formal screening interview. Of these, 256 (6%) subjects qualified for the run-in period, and 214 met the remaining enrollment criteria

Discussion

Our trial did not reveal any benefit of Ginkgo over placebo. With regard to SKT and CGI, we found small differences after 24 weeks of treatment in favor of Ginkgo. These differences were neither statistically significant nor clinically meaningful. The difference was also negligible with respect to NAA. Adjustment for possible confounding by several prognostic variables did not alter these results. After 12 weeks of follow-up, a small but statistically significant effect was registered for SKT

Acknowledgements

We are indebted to A. Versantvoort, E. Douven, and M. Moll for assistance during the data collection phase (screening interviews), to J. Kleijnen for his role in initiating the Maastricht Ginkgo Trial, to S. van de Crommert for assistance in data processing and analysis, to the patients and their relatives and to the management and the nursing staff teams of the participating homes for the elderly for their cooperation and involvement in data collection, to the interviewers appointed to the

References (39)

  • DSM-III-R: diagnostic and statistical manual of mental disorders

    (1987)
  • Mental and behavioural disorders (including disorders of psychological development): clinical descriptions and diagnostic guidelines

    ICD-10: tenth revision of the International Classification of Diseases, Chapter V (F)

    (1991)
  • T.H. Crook et al.

    Diagnosis and assessment of age-associated memory impairment

    Clin Neuropharmacol

    (1990)
  • M. Zaudig

    A new systematic method of measurement and diagnosis of “mild cognitive impairment” and dementia according to ICD-10 and DSM-III-R criteria

    Int Psychogeriatr

    (1992)
  • V.C. Hachinski et al.

    Cerebral blood flow in dementia

    Arch Neurol

    (1975)
  • J.E. Overall et al.

    The SKT neuropsychological test battery

    J Geriatr Psychiatry Neurol

    (1992)
  • T.H. Crook et al.

    Assessment of memory complaint in age-associated memory impairment: the MAC-Q

    Int Psychogeriatr

    (1992)
  • J.I. Sheik et al.

    Geriatric Depression Scale (GDS): recent evidence and development of a shorter version

  • W.J. Burke et al.

    The short form of the Geriatric Depression Scale: a comparison with the 30-item form

    J Geriatr Psychiatry Neurol

    (1991)
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