Meta-analysis of the Effects of Ginkgo Extract on Behavioral and Psychological Symptoms of Dementia

Behavioral and psychological symptoms of dementia (BPSD) are characterized by symptoms of aggression, agitation, and psychosis, which typically decrease the quality of life for the patient while increasing caregiver distress, the risk for nursing home admission, and financial burden on the healthcare system. BPSD is a treatment target for patients with dementia. In conventional medicine, pharmacological management of anti-dementia drugs (i.e., acetylcholinesterase inhibitors, memantine), antidepressants, and select antipsychotics has proven beneficial for this patient population. The agitation has been observed in patients with dementia who receive the selective serotonin reuptake inhibitor (commonly referred to as “SSRI”) citalopram. EGb 761® (Dr. Willmar Schwabe GmbH & Co. KG; Karlsruhe, Germany) is a ginkgo (Ginkgo biloba, Ginkgoaceae) leaf extract. The extract contains 22.0-27.0% ginkgo flavonoids calculated as ginkgo flavone glycosides and terpene lactones, consisting of 2.8-3.4% ginkgolides A, B, and C, 2.6-3.2% bilobalide, and less than 5 ppm of ginkgolic acids. Studies show that EGb 761 is an effective treatment for BPSD. The purpose of this meta-analysis was to evaluate the effects of EGb 761 on individual BPSD; namely, an overall reduction of symptoms, reduction of symptoms present at baseline, and the prevention of newly emerging symptoms. Also, symptoms of caregiver burden were evaluated.

The following databases were searched: PubMed/Medline (from inception through December 2013), EMBASE (from January 2006 through December 2013), and PASCAL (from inception through December 2013). The search was updated June 2016. The following search terms were used: (ginkg* OR gingk*) AND clinical trial(pt) for PubMed, ((ginkg* OR gingk*) NOT medline(sb)) AND (clinical* OR trial OR randomized) for PubMed excluding Medline, (GINKGO OR GINGKO), AND (HUMAN/CT OR HOMME/CTFR) for PASCAL, and (ginkgo or gingko) AND CT = (CLINICAL TRIAL; CLINICAL STUDY; DOUBLE BLIND PROCEDURE) AND py > 2005 for EMBASE. Reference sections were screened. The manufacturer of EGb 761 was contacted for any unpublished studies. Included studies met the following criteria: (1) randomized, placebo-controlled clinical trials of EGb 761; (2) duration of ≥ 20 weeks; and (3) included patients with dementia (probable Alzheimer’s disease [AD], probable vascular dementia [VaD], or possible AD with cerebrovascular disease) and clinically significant BPSD (Neuropsychiatric Inventory [NPI] total score ≥ 6). A meta-analysis was conducted. The primary outcome measure was single-item scores on the NPI (a 12-item inventory of the presence and severity of behavioral changes in patients with dementia).

Four studies met the inclusion criteria. The authors do not say how many articles were excluded. All four studies were similarly designed (i.e., multicentered, randomized, double-blind, placebo-controlled), included patients with mild to moderate dementia, and evaluated 240 mg/day EGb 761 or placebo for 22 weeks or 24 weeks. The manufacturer of EGb 761, Dr. Willmar Schwabe GmbH & Co KG, provided individual patient data from all studies for use in the meta-analysis. The 12-item inventory designed to assess the presence and severity of altered behavior associated with dementia upon which study patients were evaluated (NPI) assessed the following signs and symptoms: delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, sleep and nighttime behavior disorders, and appetite and eating disorders. All included patients scored 35 or less on the Test for the Early Detection of Dementia with the Differentiation from Depression; had scores ranging from 9-23 on the SKT short cognitive performance test; and had clinically significant BPSD, denoted by a composite score of ≥ 6 on the NPI with at least one item score (other than delusions or hallucinations) with a value ≥ 3.

While 1628 patients were randomly assigned in the four trials evaluated, the meta-analysis included data from 1598 patients (n = 796, EGb 761; n = 802, placebo). The mean age was 66 years ± 9 years, and ≥ 67% of each group were women. There were no significant differences between groups at baseline. At the study’s end, the EGb 761 group had significantly greater improvement from baseline compared with the placebo group on the NPI composite score and caregiver distress scores (P values not reported).

  • For net effects of individual NPI composite scores, the EGb 761 group had significant improvement from baseline compared with the placebo group in the incidence of apathy (P < 0.001) > disturbance in sleep/nighttime behavior (P < 0.001) > depression (P < 0.001) > anxiety (P < 0.001) > irritability/lability (P < 0.001).

o   There were minimal changes in the incidence of delusions, hallucinations, and elation/euphoria, as well as in those endpoints that were low at baseline (i.e., disinhibition, aberrant motor behavior, and appetite/eating).

  • For net effects of individual caregiver distress scale scores, the EGb 761 group had significant improvement in the incidence of symptoms from baseline compared with the placebo group for depression (P < 0.001) > disturbance in sleep/nighttime behavior (P < 0.001) > apathy (P < 0.001) > anxiety (P < 0.001) > irritability/liability (P < 0.001).
  • Similarly, for individual NPI composite scores, the EGb 761 group had significantly greater symptom improvement from baseline compared with the placebo group for aberrant motor behavior (P < 0.001) > apathy (P < 0.001) > depression (P < 0.001) > agitation (P < 0.001) > disturbance in sleep/nighttime behavior (P < 0.001) > anxiety (P < 0.001).
  • For individual caregiver distress scale scores, the EGb 761 group had significantly greater symptom improvement from baseline compared with the placebo group for agitation (P < 0.001) > depression (P < 0.001) aberrant motor behavior (P < 0.001) > disturbance in sleep/nighttime behavior (P < 0.001) > anxiety (P < 0.001) > apathy (P < 0.001).
  • For individual NPI composite scores for symptoms not originally present at baseline but emerging during the study period, the incidence at the study’s end was significantly lower in EGb 761 group compared with the placebo group for depression (P < 0.001) > apathy (P = 0.002) > disinhibition (P = 0.001) > disturbance in sleep/nighttime behavior (P = 0.258).
  • For individual caregiver distress scale scores for symptoms not originally present at baseline but emerging during the study period, the incidence at the study’s end was significantly lower in EGb 761 group compared with the placebo group for depression (P < 0.001) > apathy (P = 0.022) > disinhibition (P = 0.004) > disturbance in sleep/nighttime behavior (P = 0.004).
  • Overall, the symptoms that were most prevalent at baseline improved in 50-60% of the EGb 761 group and 30-40% of the placebo group.

The authors conclude that 22 or 24 weeks of treatment with EGb 761 provided significant benefit for nine out of 12 symptoms of individual NPI composite and caregiver distress scores compared with placebo. The mechanism of action of how EGb 761 improves each symptom has not been confirmed but may be related to modulation of neurotransmitter systems.

This study has several strengths that make it unique and of high scientific value. (1) The authors were able to obtain raw data from all studies to conduct the meta-analysis. (2) The four included studies were homogeneous. (3) The population size was relatively large. (4) All included studies evaluated the same dose and preparation of ginkgo.

This article also had some limitations. (1) The authors did not report how many articles were located in their original search. (2) The authors did not provide P values of the total NPI composite and caregiver distress scores. (3) The search was English-language only so some studies may have been missed. (4) Considering that the authors had access to raw data, it would have been beneficial if they had conducted a meta-analysis of safety. An analysis of risk/benefit is always of value and this study missed that opportunity.

Two of the authors (Mueller and Hoerr) are employees of Dr. Willmar Schwabe GmbH & Co. KG, and the others have received speakers’ honoraria.

Resource:

Savaskan E, Mueller H, Hoerr R, von Gunten A, Gauthier S. Treatment effects of Ginkgo biloba extract EGb 761® on the spectrum of behavioral and psychological symptoms of dementia: a meta-analysis of randomized controlled trials. Int Psychogeriatr. September 21, 2017:1-9. doi: 10.1017/S1041610217001892.

 

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Systematic Review of Ginkgo Finds Potential Treatment for Dementia

Dementia encompasses a wide range of symptoms associated with a decline in memory and loss of the ability to perform everyday activities in elderly populations. Alzheimer’s disease (AD) and vascular dementia (VD) make up the vast majority of dementia cases. Ginkgo (Ginkgo biloba, Ginkgoaceae) leaf extract (GbE) has become one of the most widely used herbal remedies for dementia. Thus, many clinical trials have already examined the effects of GbE on dementia, and many systematic reviews (SRs) have analyzed these trials. This study sought to provide a comprehensive assessment of the effectiveness of GbE in the treatment of dementia based on the evidence provided in the SRs.

All SRs which evaluated the efficacy and effectiveness of GbE as treatment (not prevention) of patients with diagnosed dementia, AD and/or VD, or mild cognitive impairment (MCI) were included. SRs were eligible only if they included the use of statistical methods (i.e., meta-analysis) to analyze randomized controlled trial (RCT) data. SRs were included whether GbE was administered alone or in combination with drugs. There were no limitations on dosage, and GbE could be administered orally or intravenously. PubMed/MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Database of Abstracts of Reviews of Effects (DARE), and Google Scholar were searched from inception to June 2016.

In total, 59 RCTs were reviewed, with patients ranging from those with any form of dementia, dementia with behavioral and psychological symptoms, cognitive impairment, or AD. Twelve SRs met the inclusion criteria; all included only RCTs (of which most were placebo-controlled trials). The included SRs were published between 2009 and 2016, and they were performed in China, Germany, Japan, and the United Kingdom. The standardized extract EGb 761® (Dr Willmar Schwabe GmbH & Co. KG; Karlsruhe, Germany) was used in many RCTs, with six SRs including only RCTs that used EGb 761. Intervention duration varied from two to 52 weeks, and dosing varied from 60 mg/day to 600 mg/day.

Outcomes of interest varied but included one or more of the following: cognitive performance, activities of daily living (ADLs), clinical global impression, quality of life (QOL), and safety. With the exception of three SRs1-3 all remaining SRs showed the statistically significant effectiveness of GbE on cognitive performance in people with dementia. Eight SRs evaluated the effect of GbE on ADLs, and, apart from one SR,3 seven SRs showed a statistically significant effect of GbE on ADLs in people with dementia. Five SRs evaluated the effect of GbE on clinical global impression of dementia, of which three showed a statistically significant effect of GbE. Of the five SRs that evaluated QOL, two concluded there was no significant difference in QOL, two did not pool the QOL data, and only one SR pooling data from two RCTs suggested a beneficial effect of GbE on QOL. Eight SRs evaluated the safety of GbE, and none found any significant difference in adverse events or side effects compared to placebo.

Seven SRs included RCTs in which GbE was administered for at least 22 weeks, and the data reported in these SRs consistently favored the beneficial effects of GbE. The five SRs in which GbE was administered for less than 22 weeks reported data that were “quite inconsistent.” This study found no particular evidence suggesting a beneficial effect of GbE on cognitive performance, ADLs, or clinical global impression when GbE was administered for less than 22 weeks. In addition, few SRs showed a beneficial effect of GbE at a dose less than 200 mg/day. In fact, four SRs consistently showed a beneficial effect of GbE on cognitive performance at a dose greater than 200 mg/day (usually 240 mg/day). Few SRs indicated a beneficial effect of GbE on ADLs and clinical global impression at a dose less than 200 mg/day.

The quality of SRs was evaluated using the AMSTAR (Assessment of Multiple Systematic Reviews) tool, and overall, the majority of reviews were found to be of good or acceptable quality. However, many of the reviewed RCTs in these SRs were of poor quality and had a high risk of bias, meaning the overall quality of evidence reviewed was low to moderate. That being said, based on the evidence gathered that met inclusion criteria, this overview found GbE to have beneficial effects over placebo on cognitive performance, ADLs, and clinical global impression when administered at a dose greater than 200 mg/day for 22 weeks or more. Globally, over 46 million people were living with dementia in 2015, and this number is expected to reach 131.5 million by 2050.4 With no cure or prevention yet found, future research is warranted. In order to better assess GbE efficacy as a treatment for dementia, future studies should take the beneficial dosing and intervention length found by this overview into account.

References

1Yang Z, Li W, Huang T, Chen J, Zhang X. Meta-analysis of Ginkgo biloba extract for the treatment of Alzheimer’s disease. Neural Regen Res. 2011;6(15):1125-1129.

2Wang BS, Wang H, Song YY, et al. Effectiveness of standardized Ginkgo biloba extract on cognitive symptoms of dementia with a six-month treatment: a bivariate random effects meta-analysis. Pharmacopsychiatry. 2010;43(3):86-91. doi: 10.1055/s-0029-1242817.

3Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. January 21, 2009;(1):CD003120. doi: 10.1002/14651858.CD003120.pub3.

4Dementia statistics. Alzheimer’s Disease International website. Available at: https://www.alz.co.uk/research/statistics. Accessed September 11, 2017.

Yuan Q, Wang CW, Shi J, Lin ZX. Effects of Ginkgo biloba on dementia: An overview of systematic reviews. J Ethnopharmacol. January 2017;195:1-9.