Herrschaft H, Nacu A, Likhachev S, Sholomov I, Hoerr R, Schlaefke S. Ginkgo biloba extract EGb 761^® in dementia with neuropsychiatric features: A randomised, placebo-controlled trial to confirm the efficacy and safety of a daily dose of 240 mg. J Psychiatr Res. 2012;46(6):716-723.

Ginkgo (Ginkgo biloba) extract EGb 761^® (Dr. Willmar Schwabe GmbH & Co. KG; Karlsruhe, Germany) has many mechanisms of action that may interfere with the pathomechanisms of Alzheimer's disease (AD) and dementia. The objective of this randomized, placebo-controlled, double-blind, multicenter study was to confirm the findings of an earlier study¹ and to further substantiate clinically relevant treatment effects on cognition and psychopathology in patients with AD and vascular dementia (VaD), both associated with neuropsychiatric symptoms (NPS).

The study recruited outpatients (n = 410; aged ≥ 50 years) from 17 psychiatry or neurology clinics in 3 countries with Russian-speaking populations (Republic of Belarus, Republic of Moldova, and the Russian Federation). These countries were chosen because cholinesterase inhibitor use was not common, and it was possible to have untreated patients with dementia who speak the same language rapidly recruited into a placebo-controlled study. Included patients had mild-to-moderate symptomatic AD or VaD for ≥ 6 months, as diagnosed via the following criteria: (a) probable AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA), (b) possible AD with cerebrovascular disease (CVD) as defined by the National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences (NINDS-AIREN), or (c) probable VaD according to NINDS-AIREN. An MRI scan, consistent with the diagnosis of AD, VaD, or AD with CVD and without evidence of other brain lesions, recorded ≤ 1 year prior to the screening visit, had to be available. Also, patients had to have the following scores: score ≤ 35 on cognitive impairment in at least 2 domains of the Test for the Early Detection of Dementia with Discrimination from Depression (TE4D), a score of 9-23 (= mild to moderate) on the Syndrom-Kurztest (SKT) short cognitive performance test, a score of < 6 on the Clock-Drawing Test (CDT), and a total score of ≥ 6 on the 12-item Neuropsychiatric Inventory (NPI), with a score of ≥ 4 on at least 1 of the following items: "anxiety," "apathy/indifference," "irritability/lability," or "depression/dysphoria."

Included patients also needed to have a caregiver who could ensure study compliance. Patients were excluded from the study if they had other types of dementia or neurological disorders; major short-term fluctuations in symptom severity; current or recent major depression or other psychiatric disorder; severe or insufficiently controlled cardiovascular, renal, or hepatic disorder; diabetes; anemia; thyroid dysfunction; active malignant disease; HIV; syphilis; or gastrointestinal disease with uncertain absorption. Treatment with other anti-dementia drugs; cognitive enhancers; cholinergic, anticholinergic, or hemorheologically active drugs; anti-Parkinson's drugs; or ginkgo products was prohibited during the clinical trial and for ≥ 8 weeks preceding randomization.

After a 4-week washout and baseline assessment period, patients were treated with a single dose of 240 mg of EGb 761 or placebo in the morning for 24 weeks. EGb 761 contains 22-27% ginkgo flavonoids calculated as ginkgo flavone glycosides and 5-7% terpene lactones consisting of 2.8-3.4% ginkgolides A, B, and C, and 2.6-3.2% bilobalide. EGb 761 contains < 5 ppm ginkgolic acids. Efficacy assessments were conducted at baseline, 12 weeks, and 24 weeks. The primary outcome measures were the SKT and NPI. The secondary outcome measures were the NPI caregiver distress test; the Clinical Global Impression of Change (CGIC) as adapted by the AD Cooperative Study (ADCS); the AD Activities of Daily Living International Scale (ADL-IS); the DEMQOL-Proxy (dementia health-related quality-of-life scale proxy-report); and the Verbal Fluency Test.

The groups were well balanced with regard to medical history and concomitant medications. Compliance was excellent for both groups. Most patients had concomitant diseases and were taking medications for them.

For the primary outcome measures, there were clinically and statistically meaningful improvements in the SKT total score and NPI score for patients treated with EGb 761 compared with placebo (P < 0.001 for both) at 24 weeks. Clinically significant responses were observed more frequently among EGb 761-treated patients (SKT: 43%, NPI: 57%) than in those taking placebo (SKT: 23%, NPI: 39%). The response rates and improvements were similar for patients with probable AD and those with possible AD with CVD or probable VaD. Similarly, all of the secondary efficacy measures showed a significant improvement with EGb 761 treatment compared with placebo treatment at 24 weeks (most were P < 0.001), including improved ability to cope with the demands of everyday living, improved quality of life, and clinicians' global judgment. The only measure that was not different between treatment groups was the 11-point box scale of tinnitus, yet the average level of tinnitus was rather low at baseline. There was no relationship between age and any outcome measure.

Adverse events (AEs) were reported by approximately 40% of both treatment groups. There were no significant differences in the incidences of AEs except that the placebo group had more reports of dizziness. There were no AE reports of bleeding or impaired blood clotting. There were 3 serious AEs; all were judged to be related to concomitant conditions and unrelated to the trial medications. There were no conspicuous or systematic changes in the physical and neurological examination, 12-lead electrocardiogram (ECG), blood pressure, heart rate, or laboratory tests.

The authors conclude that this dose of EGb 761 improves cognitive performance and psychiatric symptoms of patients with mild-to-moderate AD with NPS or VaD with NPS. The authors state that the patient sample represents a population that would be found in daily practice. The findings are promising particularly since a single daily dose was used (compliance decreases as doses/day increases), the population was inclusive of many types of dementia, and because the results confirm the findings of another study¹ with an identical design.



—Heather S. Oliff, PhD

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