Efficacy and tolerability of a once daily formulation of Ginkgo biloba extract EGb 761® in Alzheimer's disease and vascular dementia: results from a randomised controlled trial.

INTRODUCTION: A 24-week randomised controlled trial was conducted to assess the efficacy of a 240 mg once-daily preparation of Ginkgo biloba extract EGb 761® in 404 outpatients ≥ 50 years diagnosed with mild to moderate dementia (SKT 9-23), Alzheimer's disease (AD) or vascular dementia (VaD), with neuropsychiatric features (NPI total score ≥ 5). METHODS: Separate analyses were performed for diagnostic subgroups (probable or possible AD; VaD). RESULTS: 333 patients were diagnosed with AD and 71 with VaD. EGb 761® treatment was superior to placebo with respect to the SKT total score (drug-placebo differences: 1.7 for AD, p<0.001, and 1.4 for VaD, p<0.05) and the NPI total score (drug-placebo differences: 3.1 for AD, p<0.001 and 3.2 for VaD, p<0.05). Significant drug-placebo differences were found for most secondary outcome variables with no major differences between AD and VaD subgroups. Rates of adverse events in EGb 761® and placebo groups were essentially similar. CONCLUSION: EGb 761® improved cognitive functioning, neuropsychiatric symptoms and functional abilities in both types of dementia.

Baseline neuropsychiatric symptoms are effect modifiers in Ginkgo biloba extract (EGb 761®) treatment of dementia with neuropsychiatric features. Retrospective data analyses of a randomized controlled trial.

Previous studies suggested that EGb 761® may be more effective when dementia is associated with neuropsychiatric features. To find out whether treatment effects correlate with neuropsychiatric symptom burden at baseline, retrospective analyses of data from a 24-week randomized, placebo-controlled, double-blind clinical trial of EGb 761® (240 mg once daily) were performed. 410 outpatients with mild to moderate AD, VaD or AD with cerebrovascular disease, each associated with neuropsychiatric features, were enrolled. Patients scored 5 or above on the NPI, with at least one item score being ≥3, and between 9 and 23 on the SKT cognitive test battery. Correlations between the NPI composite score at baseline and other efficacy variables were calculated. Regression analyses with the NPI composite score as regressor and efficacy variables as dependent variables were performed. Correlations between changes from baseline and NPI baseline scores were weak to modest, but conspicuously different between active drug and placebo groups. The slopes of the regression lines for the EGb 761® and the placebo groups showed qualitative and statistically significant differences: With increasing NPI baseline scores there was faster deterioration in the placebo group and thus more net benefit from treatment for the EGb 761® group.

World psychiatric association section of old age psychiatry consensus statement on ethics and capacity in older people with mental disorders.

The World Psychiatric Association (WPA) Section of Old Age Psychiatry, since 1997, has developed Consensus Statements relevant to the practice of Old Age Psychiatry. Since 2006 the Section has worked to develop a Consensus Statement on Ethics and Capacity in older people with mental disorders, which was completed in Prague, September 2008, prior to the World Congress in Psychiatry. This Consensus meets one of the goals of the WPA Action Plan 2008-2011, "to promote the highest ethical standards in psychiatric practice and advocate the rights of persons with mental disorders in all regions of the world". This Consensus Statement offers to mental health clinicians caring for older people with mental disorders, caregivers, other health professionals and the general public the setting out of and discourse in ethical principles which can often be complex and challenging, supported by practical guidance in meeting such ethical needs and standards, and to encouraged good clinical practice.

Ginkgo biloba extract EGb 761(R), donepezil or both combined in the treatment of Alzheimer's disease with neuropsychiatric features: a randomised, double-blind, exploratory trial.

OBJECTIVE: This randomised, double-blind exploratory trial was undertaken to compare treatment effects and tolerability of EGb 761(R), donepezil and combined treatment in patients with AD and neuropsychiatric features. METHOD: We enrolled 96 outpatients, aged 50 years or above, who met the NINCDS/ADRDA criteria for probable AD, scored below 36 on the TE4D, a screening test for dementia, below 6 on the Clock-Drawing Test (CDT) and between 9 and 23 on the SKT, a cross-culturally validated cognitive test battery. They scored at least five on the 12-item Neuropsychiatric Inventory (NPI). EGb 761(R) (240 mg per day), donepezil (initially 5 mg, after 4 weeks 10 mg per day) or EGb 761(R) and donepezil combined (same doses) were administered for 22 weeks. RESULTS: Changes from baseline to week 22 and response rates were similar for all three treatment groups with respect to all outcome measures (SKT, NPI, total score and activities-of-daily-living sub-score of the Gottfries-Bråne-Steen Scale, Hamilton Rating Scale for Depression, CDT and Verbal Fluency Test). An apparent tendency in favour of combination treatment warrants further scrutiny. Compared to donepezil mono-therapy, the adverse event rate was lower under EGb 761(R) treatment and even under the combination treatment. CONCLUSION: These exploratory findings helped to develop three hypotheses that will have to be proven in further studies: (1) there is no significant difference in the efficiency between EGb 761(R) and donepezil, (2) a combination therapy will be superior to a mono-therapy with one of both substances and (3) there will be less side effects under a combination therapy than under mono-therapy with donepezil.

Treatment Target Test Dementia (3TD).

OBJECTIVE: So far goal-oriented therapy in dementia cannot be measured sufficiently. There are no tests that detect a profile of capacities that could describe the targets of training. Thus, it was aimed to develop a test that uncovers a profile of capacities in patients suffering from dementia. METHODS: Three groups of subjects (n = 156), 30 patients suffering from dementia of the Alzheimer type, 28 from depressive disorder and 98 healthy age-comparable controls were included in the study. Building on already existing tests, items were developed to cover intelligence, visuo-spatial abilities, cognitive and social problem solving, emotional and executive abilities. All subjects were investigated with the Training Target Test Dementia (3TD). To calculate convergence validity, the Test for the Early Detection of Dementia from depression (TE4D) and the Beck Depression Inventory were assessed. Descriptively, profiles were calculated. Group differences were studied with the Kruskal-Wallis and the Mann-Whitney-U-test. RESULTS: Characteristic neuropsychological capacity profiles were found within the three groups. Differences between the groups were significant for all subtests. Significantly, the 3TD separated patients with dementia from controls. It reached high sensitivity and acceptable specificity. The convergence validity to the TE4D was significant (r = 0.77). CONCLUSIONS: The capacity profiles detected may allow for specified therapeutic modules to be scheduled. Moreover, the 3TD will be suitable to discriminate between patients suffering from dementia, depression as well as healthy age-comparable controls. For therapeutic improvement, further investigation will be needed to prove its sensitivity.

The impact of drugs against dementia on cognition in aging and mild cognitive impairment.

OBJECTIVE: To define the actual knowledge of the impact of drugs for the treatment of dementia on the improvement of cognition in aging and mild cognitive impairment. METHOD: We conducted a Medline search for studies with the parameters drug and cognition. Only drugs that had demonstrated cognition improvements in dementia according to actual methodological standards were included. Drugs had to be approved in at least one American or European nation. RESULTS: Donepezil, galantamine, Ginkgo biloba EGb 761 (definition see editorial), memantine and rivastigmine fulfilled these criteria. There were no systematic investigations on the effects of these drugs on cognition in healthy adults or patients with mild cognitive impairment (MCI). Regarding Ginkgo biloba, two studies on MCI patients could be identified. In healthy adults, we could only include one study investigating donepezil and seven investigating Ginkgo biloba EGb 761. According to the findings, donepezil significantly increased the percentage of REM sleep and REM density, whereas REM latency was reduced. This was interpreted as a sign of improved cognition. Ginkgo biloba EGb 761 improved cognition in healthy controls according to Delayed Free Recall and Delayed Recognition of the WAIS-III and the Color Naming of the Stroop Test as well as in MCI in Digit Copying, Dual Coding Task and speed of response on a computerized version of a classification task. The highest effects were observed after 6 weeks of treatment with 180 mg/d. CONCLUSIONS: Due to the lack of standard procedures for investigating cognition improvement in healthy aging, results have to be interpreted cautiously. In healthy adults as well as in individuals categorized as having MCI, Ginkgo biloba EGb 761 improved cognition in some but not all neuropsychological tests. The single positive result with donepezil raises hope that other drugs may also contribute to cognitive improvement, even in healthy adults. However, the data do not allow any conclusions regarding an improvement following a specific "neuropsychological cluster." Studies on prevention have not been completed so far.

[Dementing disorders. What benefits do the new anti-dementia drugs have?]. / Demenzerkrankungen. Was bringen die neuen Antidementiva?

A critical analysis of the latest studies and meta-analyses dealing with antidementia agents, show that the efficacy of donepezil, galantamine, ginkgo biloba EGb 761, memantine, rivastigmine and tacrine in Alzheimer's disease is adequately confirmed. With the exception of tacrine, none of these substances are commonly associated with severe side effects. In the case of vascular dementia, the efficacy of ginkgo biloba EGb 761 and memantine has been demonstrated. Studies on the effectiveness of the cholinesterase inhibitors for this indication have been initiated. Antidementia agents can delay progression of the disease by about 6 to 12 months. Further studies are needed to confirm evidence of a prophylactic effect and a synergistic action of combinations.

EEG-correlates of facial affect recognition and categorisation of blurred faces in schizophrenic patients and healthy volunteers.

The ability to recognise emotional expressions of faces and the ability to categorise blurred and non-blurred faces and complex objects was tested in 16 schizophrenic in-patients and 16 healthy volunteers. EEGs were recorded during performance of the tasks and event-related potentials were compared between groups. Patients performed worse than healthy volunteers in recognition of facial affect but not in categorisation of blurred faces. Furthermore, within a 180-250ms latency range patients showed reduced amplitudes during affect recognition compared with controls but not during categorisation of blurred faces. Amplitudes recorded at frontal electrode sites were associated with performance in facial affect recognition. These results provide a first clue to the neurophysiological basis of the widely reported facial affect recognition deficit in schizophrenic patients.

[Development and validation of a test for early diagnosis of dementia with differentiation from depression (TFDD)]. / Entwicklung und Validierung eines Tests zur Früherkennung der Demenz mit Depressionsabgrenzung (TFDD).

Psychometric tests used for the early detection of dementia often are seen as too difficult or too complex. Classical neuropsychologic tests were not developed for this purpose. Sensitivity and specificity to discriminate "healthy" vs. "ill" are low. For measuring both dementive and depressive symptoms, so far no test has been published. The objective of this study was to develop a sensitive and specific test for dementia that is easy to administer and to evaluate. Moreover, it should discriminate dementia from depressive pseudodementia. With respect to former studies, items were selected that recognized patients in the beginning of the disease. Additionally, depressive symptoms were rated. With the items for dementia, 88 patients with dementia of the Alzheimer type, 52 patients with depressive disorder and 37 healthy elderly controls were investigated. In this group of already diagnosed patients, the test reached a sensitivity and specificity of 100 percent (healthy elderly controls vs. patients with Alzheimer's disease: n = 125, U = 0, p < 0.001; patients with depressive disorder vs. patients with Alzheimer's disease: n = 140, U = 0, p < 0.001; healthy elderly controls vs. patients with depressive disorder: n = 89, U = 485.5, p < 0.001). For the dementia items, the inter-rater-reliability was rs = 0.996 (p < 0.001, n = 18), for the depression items it was rs = 0.753 (n = 18, p < 0.001). The test-retest-reliability was rs = 0.868 (p < 0.001, n = 35) for the dementia items and rs = 0.7 (n = 8, p < 0.05) for the depression items. These validation data will make the test useful for practitioners. Its ability to discriminate patients suffering from dementia of the Alzheimer type from healthy controls is comparable to tests consuming more time.

A comparison of ADAS and EEG in the discrimination of patients with dementia of the Alzheimer type from healthy controls.

Neuropsychometric tests (for instance the Alzheimer's Disease Assessment Scale, ADAS) and the EEG are often used in the diagnostic procedure of dementia. The validity of the instruments is only poorly investigated. The study aimed to investigate the accuracy of the discrimination between healthy controls and patients with dementia of the Alzheimer type (DAT) by ADAS and EEG. Thirty-six patients with DAT and 44 healthy controls were included. In a discriminant analysis of the 21 ADAS items and 18 EEG parameters (6 frequency bands, 12 topographic parameters), 6 ADAS items turned out to discriminate both groups with 100% sensitivity and specificity (remembering instructions, depression, following commands, pacing, restlessness and word finding difficulties). Regarding EEG parameters, 4 (topography of beta- and delta-activity and amplitude of delta-activity) led to a sensitivity and specificity of over 90%. Thus, both methods demonstrated an excellent discrimination between healthy controls and DAT. The slightly higher discrimination with the ADAS may depend on its closer relation to clinical symptoms. However, the EEG measuring functional activity reached nearly the same result. Both methods provide complementary information. A combination of both methods in the diagnostic procedure to detect dementia is recommended.

Electrophysiological correlates of emotional and structural face processing in humans.

In order to study brain potentials related to decoding of facial expressions of emotions and those, related to basic perception of faces 16 right-handed subjects performed tasks on facial emotion recognition and perception of blurred faces and objects. Electroencephalograph (EEG) recordings during performance of the tasks revealed similar event-related potentials during the presentation of faces at 120 and 170 ms after stimulus onset in both of the tasks but significant differences in amplitudes between 180 and 300 ms. Whereas faces in the emotion recognition task produced high amplitudes in that latency range, potentials in response to faces in the blurred object condition were virtually absent. These data point to the assumption that decoding of facial expressions starts early in the brain and might be processed separately from basic stages of face perception.

Neuropsychometric tests in cross sectional and longitudinal studies - a regression analysis of ADAS - cog, SKT and MMSE.

INTRODUCTION: In clinical and drug studies, different neuropsychometric tests are used. So far, no empirical data have been published to compare studies using different tests. The purpose of this study was to calculate a regression formula allowing a comparison of cross-sectional and longitudinal data from three neuropsychometric tests that are frequently used in drug studies (Alzheimer's Disease Assessment Scale, ADAS-cog; Syndrom Kurz Test, SKT; Mini Mental State Examination, MMSE). METHOD: 177 patients with dementia according to ICD10 criteria were studied for the cross sectional and 61 for the longitudinal analysis. Correlations and linear regressions were calculated between tests. Significance was proven with ANOVA and t-tests using the SPSS statistical package. RESULTS: Significant Spearman correlations and slopes in the regression occurred in the cross sectional analysis (ADAS-cog-SKT r(s) = 0.77, slope = 0.45, SKT-ADAS-cog slope = 1.3, r2 = 0.59; ADAS-cog-MMSE r2 = 0.76, slope = -0.42, MMSE-ADAS-cog slope = -1.5, r2 = 0.64; MMSE-SKT r(s) = -0.79, slope = -0.87, SKT-MMSE slope = -0.71, r2 = 0.62; p<0.001 after Bonferroni correction; N = 177) and in the longitudinal analysis (SKT-ADAS-cog, r(s) = 0.48, slope = 0.69, ADAS-cog-SKT slope = 0.69, p<0.001, r2 = 0.32, MMSE-SKT, r(s) = 0.44, slope = -0.41, SKT-MMSE, slope = -0.55, p<0.001, r2 = 0.21). CONCLUSIONS: The results allow calculation of ADAS-scores when SKT scores are given, and vice versa. In longitudinal studies or in the course of the disease, scores assessed with the ADAS-cog and the SKT may now be statistically compared. In all comparisons, bottom and ceiling effects of the tests have to be taken into account.

Differential diagnosis of aging, dementia of the Alzheimer type and depression with EEG-segmentation.

EEG segmentation can be used to measure altered brain function in aging and diseases of the brain. The parameter 'number of different segments' makes clear how many different potential fields are involved in brain activity during a given period of time. It should represent effects of aging and disease. To prove this assumption, 11 young and 10 aged controls, 12 patients with mild dementia of the Alzheimer type (DAT), 10 young and 12 aged patients with endogenous depression were included in the study. The number of different segments in the beta frequency band between 16 and 19.75 Hz was measured according to the theory of Lehmann et al. [Clinical Neurophysiology 1987;67:271-288], and the segments were classified by their location on the scalp. The Mann-Whitney U test was used for statistical comparison. Aged controls had more different segments than young controls (n = 21, U = 14, p < 0.0038). Patients with DAT had less different segments than healthy aged controls (n = 22, U = 18.5, p < 0.0061). Aged patients with endogenous depression had more different segments than patients with mild DAT (n = 24, U = 32, p < 0.021). The reduction of the number of different segments in DAT compared to controls and patients suffering from depression may be helpful for differential diagnosis. The higher number of different segments in aged versus young controls could be interpreted as a sign of increased complexity in the aged brain.

Clinical efficacy of Ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type.

Among the psychiatric illnesses associated with old age primary degenerative dementia of the Alzheimer type (DAT) has gained increasing importance in recent years. Even though a curative treatment of the disease is currently impossible, various drugs can be used to slow down its progression. In the present study the influence of oral treatment with 240 mg/day of Ginkgo biloba special extract EGb 761 (Tebonin® forte, manufactured by Dr. Willmar Schwabe, Karlsruhe) on the clinical course of DAT was investigated in a double-blind, randomized, placebo-controlled parallel-group design in 20 outpatients. The duration of treatment was 3 months. The primary outcome variable was the sum score in the SKT-test for the determination of attention and memory. Other psychometric tests (trailmaking test, ADAS, CGI) and electrophysiological investigations (EEG topography) were evaluated descriptively. Although the active-treatment group, with a mean sum score of 19.67 points in the S.K.T., had a poorer baseline level than the placebo group (18.11 points), it experienced an improvement to 16.78 points under treatment with EGb 761 whereas the placebo group deteriorated to 18.89 points. The differences between the baseline and final values formed the basis for a statistical group comparison, which gave a result favourable to EGb 761, at a significance level of p <.013. In addition to this psychometric confirmation of efficacy, certain descriptive trends were found at the psychopathological (Clinical Global Impression) and dynamic functional (EEG findings) levels, which can be interpreted as evidence of effectiveness of Ginkgo biloba special extract EGb 761 in mild to moderate dementia and of local effects in the central nervous system. Inter-group differences in the ADAS cognitive and non-cognitive subscales did not reach statistical significance, probably because of the small sample size.

Alzheimer's Disease Assessment Scale: reliability and validity in a multicenter clinical trial.

Psychometric characteristics of the Alzheimer's Disease Assessment Scale (ADAS) were examined on the basis of data from 440 patients with dementia of the Alzheimer type that were collected before treatment in a multicenter clinical drug trial. Coefficients of internal consistency of above .80 for the cognitive (ADAS-Cog) and the noncognitive section (ADAS-Noncog) indicated a high degree of homogeneity of item contents within the two assessment domains. Test-retest reliability was estimated to be .93, .98, and .96 for ADAS-Cog, ADAS-Noncog, and the total score (ADAS-Total), respectively. Reliably detectable individual changes, which were derived from the reliability estimates, were 7, 3, and 8 points for ADAS-Cog, ADAS-Noncog, and ADAS-Total, in that order. Factor analysis and correlations with MMSE, SKT, and NOSGER scores support the validity of the ADAS-Cog and ADAS-Noncog scores with regard to the cognitive and the noncognitive assessment domains. The ADAS summary scores, almost all of the cognitive items, and some of the noncognitive items discriminated significantly between stages of severity of dementia, as classified independently by MMSE and SKT scores.

The AMDP modules I-IV: recommendations for a standardized acquisition of EEG data in psychiatry. Association for Methodology and Documentation in Psychiatry.

During the last few years, the working group 'Psychophysiology' of the Association for Methodology and Documentation in Psychiatry (AMDP) discussed the possibility of the establishment of defined EEG modules in psychiatry. It was the aim to create a common data pool in order to be able to have access to larger data sets. The installation of such a common data pool was regarded as an important prerequisite for a future diagnostic application of EEG and EP data in clinical practice. The most relevant arguments are: From a statistical point of view, multivariate investigations can be improved when relatively large data sets are available. Subgrouping of patients is facilitated. Different centers have access to different populations of patients. Furthermore, compliance with the recommendations contributes to a reduction in misunderstanding and false interpretation of other investigators' results. The working group 'Psychophysiology' of the AMDP now recommends EEG modules to be registered in psychiatry. The recommendations are based on investigations using these modules in clinical research and practice as well as several years of discussion within the working group. Four AMDP modules (I-IV) are presented: MI: resting EEG (closed eyes), MII: resting EEG (eyes open), MIII: EEG during videotracking, and MIV: EEG during choice reaction time. Recommendations for additional modules are planned in the near future: MV: EEG during geometry test, MVI: EEG during labyrinth test, and MVII: amplitude stimulus intensity function. MIII-MVI is paralleled by an EEG recording so that psychomotor performance can be measured and EEG data under different activation conditions are available. Compliance with the recommendations guarantees the possibility of access to the common data pool. Computer software is available in Berlin.

[Nootropic drug evaluation for general practice]. / Zur Nootropikabewertung für die Praxis.

Treatment with "nootropic drugs" of patients suffering from dementia is often described as arbitrary. To define the potential usefulness of nootropic drugs, effects and side effects, economic aspects in comparison to other treatment approaches were studied. A summary of literature published concerning these criteria underlines the efficacy of nootropics in improving the symptoms at the beginning and in postponing the progress of the disease. The majority of substances does not lead to severe side effects. There are not enough studies comparing the effects of the substances or on prophylactic effects. Delayed admission to care units leads to a positive cost effect of nootropics. Thus, also for economic reasons it seems advisable to treat patients with nootropics. Better effects are gained when nootropic treatment is combined with training and changing of the structure of the environment. A proposal for a rational treatment with nootropics is derived from the data.

Clinical efficacy of Ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type.

Among the psychiatric illnesses associated with old age primary degenerative dementia of the Alzheimer type (DAT) has gained increasing importance in recent years. Even though a curative treatment of the disease is currently impossible, various drugs can be used to slow down its progression. In the present study the influence of oral treatment with 240 mg/day of Ginkgo bilabo special extract EGb 761 (Tebonin forte, manufactured by Dr Willmar Schwabe, Karlsruhe) on the clinical course of DAT was investigated in a double-blind, randomized, placebo-controlled parallel-group design in 20 outpatients. The duration of treatment was 3 months. The primary outcome variable was the sum score in the SKT-test for the determination of attention and memory. Other psychometric tests (trailmaking test, ADAS, CGI) and electrophysiological investigations (EEG topography) were evaluated descriptively. Although the active-treatment group, with a mean sum score of 19.67 points in the, S.K.T., had a poorer baseline level than the placebo group (18.11 points), it experienced an improvement to 16.78 points under treatment with EGb 761 whereas the placebo group deteriorated to 18.89 points. The differences between the baseline and final values formed the basis for a statistical group comparison, which gave a result favourable to EGb 761, at a significance level of p < .013. In addition to this psychometric confirmation of efficacy, certain descriptive trends were found at the psychopathological (Clinical Global Impression) and dynamic functional (EEG findings) levels, which can be interpreted as evidence of effectiveness of Ginkgo biloba special extract EGb 761 in mild to moderate dementia and of local effects in the central nervous system. Inter-group differences in the ADAS cognitive and non-cognitive subscales did not reach statistical significance, probably because of the small sample size.