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Apr 18, 2009 - Extracts of Ginkgo biloba are widely used for the treatment of cognitive impairment. Whereas reviews have focused on the question whether.
human psychopharmacology Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. Published online 23 June 2009 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/hup.1037

REVIEW ARTICLE

Ginkgo biloba: specificity of neuropsychological improvement—a selective review in search of differential effectsy Reiner Kaschel* University of Osnabrueck, Germany

Extracts of Ginkgo biloba are widely used for the treatment of cognitive impairment. Whereas reviews have focused on the question whether ginkgo is effective to enhance cognition in general, little is known about specificity of improvement. This might be crucial for future trials, thus enabling hypotheses about sensitive outcome measures. Therefore, this article summarizes such information, i.e. neuropsychological effects of chronic administration of ginkgo in healthy and cognitively impaired subjects of any age. Objective psychometric test results were considered if they reflected distinct cognitive functions from randomized controlled group-studies (RCT). We reviewed 29 RCTs yielding 209 placebo-drug comparisons of psychometric scores in four different cognitive domains comprising 14 sub-functions. Whereas little specific information can be obtained from trials for treatment of dementia, a pattern of pharmacological actions on cognitive processes emerges here from studies for mild cognitive impairment (MCI), depression, multiple sclerosis and healthy young and elderly subjects. There is consistent evidence that chronic administration improves selective attention, some executive processes and long-term memory for verbal and non-verbal material. Further trials should be more comprehensive as there are few data available on some cognitive functions and psychometric flaws in the selection of tests and the interpretation of their results favouring predominantly b-errors. Thus, though this pattern is encouraging it also asks for a cautious interpretation to date. Copyright # 2009 John Wiley & Sons, Ltd. key words — Ginkgo biloba; mild cognitive impairment; dementia; psychometric tests; working memory; neuropsychological improvement

INTRODUCTION Extracts of the leaves of the maidenhair tree, Ginkgo biloba, have long been used in traditional Chinese medicine for various disorders (Itil and Martorano, 1995). A standardized special extract (EGb 76111) is widely prescribed in Europe for the treatment of ageassociated cognitive decline (including dementia; Canter and Ernst, 2007) and different neurosensory and circulatory disorders it became quite popular (tinnitus, vertigo, claudicatio intermittens; cf Birks et al., 2002). Most of the available empirical research was done with this special extract, which is obtained in a multiple-step extraction process, purified to remove harmful accompanying substances, and standardized to

* Correspondence to: R. Kaschel, University of Osnabrueck, Germany. E-mail: [email protected] y Potential conflict of interest: None. This review has not been encouraged or sponsored by any pharmaceutical company. 1 Registered trade mark—Dr Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany.

Copyright # 2009 John Wiley & Sons, Ltd.

24% ginkgo-flavone glycosides and 6% terpene lactones (ginkgolides, bilobalide), the pharmacologically active constituents (DeFeudis, 1998). EGb 761 is a potent radical scavenger and antioxidant (Barth et al., 1991; Dorman et al., 1992; Dumont et al., 1992; Kampko¨tter et al., 2007; Pincemail et al., 1989; Smith and Luo, 2003). In pre-clinical studies, it has been shown to protect the brain from ischaemic/ hypoxic damage (Karcher et al., 1984; Pierre et al., 1999; Spinnewyn et al., 1986), to change the micromechanics of erythrocytes (Artmann et al., 1991), to protect mitochondria from ageing-related damage thus improving mitochondrial function and energy metabolism (Abdel-Kader et al., 2007; Eckert et al., 2003; Sastre et al., 1998). Moreover, EGb 761 inhibits a major mediator of inflammation (the so-called platelet activating factor; Akiba et al., 1998; Braquet et al., 1985; Smith et al., 1996), attenuates insulin resistance (Hoyer et al. 1999), enhances high-affinity choline uptake (Krisˇtofikova´ et al., 1992) and increases the density of hippocampal muscarinic receptors (Taylor, 1988). In recent studies, EGb 761 was found to inhibit Received 27 May 2008 Accepted 18 April 2009

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the aggregation of amyloid-b (Ab) protein and the formation of Ab oligomers (Luo et al., 2002; Wu et al., 2006). Clinical-pharmacological studies of Ginkgo biloba extracts showed a decrease in blood viscosity and improvement in haemorheology (Anadere et al., 1985; Ko¨ltringer et al., 1995), enhanced cerebral perfusion (Heiss and Zeiler, 1978; Tea et al., 1987; Timerbaeva et al., 2000; Santos et al., 2003) and beneficial changes on the EEG (Luthringer et al., 1995; Itil and Martorano, 1995; Itil et al., 1996). Clinical-therapeutic applications are most popular for cognitive impairments of different origin. A first Cochrane meta-analysis including 33 randomized placebo-controlled trials found superiority over placebo in different domains: cognition, activities of daily living as well as mood and emotional functions in dementia and other cognitive disorders. There was ‘promising evidence of improvement in cognition and function associated with ginkgo’ (Birks et al., 2002; p. 2). This is in line with another review which stated that its use in dementia is ‘encouraging’ (Ernst and Pittler, 1999; p. 301) and the conclusion that ‘for treating cognitive impairment and dementia, the evidence suggests that ginkgo is effective’ (Ernst et al., 2006; p. 404). Although relating to a similar database, an updated Cochrane review is more sceptical: ‘There is no convincing evidence that Ginkgo biloba is efficacious for dementia and cognitive impairment. . .Evidence that Ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unconvincing’ (Birks and Grimley Evans, 2007; p. 1– 2). Similar negative evidence is stated in a review on healthy people younger than 60 years in acute as well as chronic administration (Canter and Ernst, 2007). This is again in sharp contrast to a review also examining short- and long-term administration in healthy and cognitively intact adults—‘significant positive results in 11 of 16 studies’ (Crews et al., 2005; p. 53). Taken together, there are two rather different sources of evidence for effects of Ginkgo biloba: detailed experimental data on ‘microscopic’ effects suggesting a variety of physiological effects and ‘macroscopic’ reports on clinically relevant changes in healty individuals, dementia and other cognitive disorders. Their reviews are astonishingly contradictory in the degree to which they claim that clinical evidence does exist. One of the reasons for contradictory clinical findings may have to do with the impression that both lines of research—i.e. experimental physiological in vitro and in vivo research and clinical treatment studies—do not converge. Even if outcome measures from different sources are used—e.g. changes in Copyright # 2009 John Wiley & Sons, Ltd.

power-spectra of EEG, ratings of psychopathology and psychometric measures (e.g. Itil et al., 1996)—the latter are typically reported only on a global level which prevents any speculations on the specificity of cognitive effects. This leaves a number of interesting questions unanswered, especially whether ginkgo comprises general or more specific cognition enhancing effects: if there are effects on memory—on which kind of rather different sub-systems? Whereas it is well accepted in psychology, that memory and attention are cognitive systems which share some functions in common (e.g. supervisory attentional system—central executive; cf. Solso, 2001), in most of the ginkgo-trials on healthy or clinical samples, only global measures of cognition or memory are applied. Similarily, if reliable and valid psychometric tests for distinct cognitive functions are administered, the heterogenity of memory processes is not adressed by selecting sensitive measures used in other fields, e.g. the neuropsychological rehabilitation of memory (e.g. short- or long-term memory; visual vs. verbal material; recall vs. recognition tests; Kaschel et al., 2002). Whereas the methodological quality of ginkgo-trials has much improved in many respects (Birks and Grimley Evans, 2007), less attention has been paid to the methodology of selection, application and interpretation of cognitive outcome measures (psychometric tests). For example, selection of tests is rarely guided by hypotheses, there is a lack of operationalization of distinct cognitive functions by a corresponding test, thus leading to a confusing, redundant and unstructured array of cognitive outcome measures in Ginkgo trials (cf. Crews et al., 2005; pp. 57–58). One objection to this search for specific effects might be that the diversity of physiological effects of ginkgo and the variety of disorders for which it was recommended suggests a general rather than specific cognition-enhancing effect—i.e. irrespective of age, underlying pathology or the kind of cognitive function (memory, attention, etc.). Therefore, any attempts to dissociate effects on different attentional or memory sub-functions should not be promising. There are at least two arguments why plausibility may not tell the whole story of this argument: first of all, one could reasonably expect that if physiological effects are widespread—specific effects on distinct cognitive subfunctions should not emerge. Despite some plausibility of this argument, we want to argue that there is a limited number of critical processes impaired by normal and pathological ageing (cf. dorsolateral hypothesis of normal ageing; MacPherson et al., 2002). Ginkgo might delay some of these processes and typical sites of Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

ginkgo biloba: neuropsychological effects of chronic administration

impaired function could act as a final common pathway of quite different pharmacological actions. The second argument for a general cognitionenhancing effect of ginkgo is equally plausible at a first look but points to a methodological instead of a pharmacological problem. It deals with the decision in favour of global cognitive outcome measures: most of the available literature using this methodology shows altered cognition in general, reports global scores, i.e. dementia scales which summarize cognitive sub-scales (Birks and Grimley Evans, 2007). More general measures of cognition are used in demented samples because most of the clinical trials assess global efficacy on pre-defined well-established primary endpoints as this is exactly what antidementive drugs are asked for. Furthermore, the selection of well-established dementia scales encourages interpretation and replication of results and the a priori definition of primary endpoints avoids the problem of a-errors given multiple outcome measures (e.g. instead of using a variety of psychometric tests for different cognitive domains). Moreover, seriously impaired demented patients may no longer be able to pass time-consuming, sophisticated or demanding test batteries and show floor effects. Furthermore, apart from very early stages, demented patients show deficits in rather different cognitive domains, thus disclaiming any efforts to find differential effects of drugs on specific cognitive functions. Taken together, large treatment studies preferred global tests but they did not answer the question of general versus specific effects on cognition. For example, Hofferberth (1994) reported significant improvement in a brief test of memory and attention (Syndrom-Kurz-Test) in moderately severe Alzheimers’ patients. Unfortunately it is not clear to which sub-tests or functions these effects could be attributed: nine sub-tests ranging from praxis and memory span to fluency are summed up into one—rather confounded—outcome score (cf Birks and Grimley Evans, 2007; p. 8). Instead, we want to concentrate on this question of specificity, because it could bridge the gap between experimental physiological and clinical treatment studies which yield to rather differing conclusions regarding efficacy. Fortunately, there are sources for such data as several studies are providing fine-graded cognitive outcome measures, e.g. well-established psychometric memory or attention tests (e.g. Mix and Crews, 2002). Typically, they evaluated the efficacy of ginkgo for an alleviation of cognitive deficits which were less severe than in dementia. For example, validated psychometric tests assessed effects of ginkgo in elderly persons with depression (Schubert and Halama, 1993), mild cognitive impairment (MCI) (Wesnes et al., 1987) or Copyright # 2009 John Wiley & Sons, Ltd.

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‘organic brain syndrome’ (an ill-defined largely obsolete term in the European research literature on ‘nootropics’; cf. Birks et al., 2002). Whereas other reviews have focused on the question whether ginkgo improves memory or cognition in clinical samples, looking more deeply into these psychometric results we will concentrate on the question which specific functions are improved—if any. We are interested in the targets of change, i.e. asking ‘which cognitive functions are most sensitive to the effects of ginkgo’? As there are no reasons why these should differ according to age, diagnosis or treatment duration, contrary to other reviews we made no restrictions in terms of sample characteristics. The identification of more specific cognitive effects may furnish future clinical trials: if effects on specific cognitive functions become evident, it could be tested empirically whether cognition-enhancing effects are most pronounced in certain domains. More sophisticated cognitive testing would correspond to the use of other specific outcome measures from technical sources. This could improve the currently asymetrical state of up-to-date and very specific fMRI-, PET-, SPECT- or EEG-measures used in ginkgo-trials as opposed to post-world-war II cognitive tests which often lack a theoretical as well as proper psychometric grounding. METHOD Selection of relevant studies This review is restricted to randomized double-blind placebo-controlled studies of chronic administration (>4 weeks) which provide statistical data on functionspecific cognitive tests which measure objective performance and are psychometrically based, i.e. they fulfil minimal requirements concerning their theoretical background and their quality of measurement (objectivity, reliability, validity, norms). Two search strategies were applied for this review: first we used the revised Cochrane review on ginkgo from 2007 which used different databases (Birks and Grimley Evans, 2007). No restraints were applied according to source, language and years of publication. In the Cochrane review, search terms were ‘ginkgo, tanakan, EGB-761, EGB 761, ‘‘EGB 761’’ and ginkgo’ (57 hits publication years 1976–2005). Secondly, a medline search was performed using ‘Ginkgo OR ginkgo OR ginkgo AND cognit AND clinical trial (113 hits publication years 1988–2008). Both search strategies yielded complementary information as both identified different studies. Of the final pool of 29 RCTs included Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

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in this review (see Table 2), 16 orginated from the Cochrane review whereas another 12 RCTs were identified only by Medline. Overlap was small, as only one article was found using both sources (Hofferberth, 1989). The Cochrane review yielded studies from early publication years 1986–2000 (Brautigam et al., 1998; Bru¨chert et al., 1991; Gessner et al., 1985; Gra¨ßel, 1992; Halama, 1991; Hartmann and Frick, 1991; Hofferberth, 1989; Hofferberth, 1991; Hofferberth, 1994; Israe¨l et al., 1987, 1995; Oswald et al., 1997; Rai et al., 1991; Schubert and Halama, 1993; van Dongen et al., 2000; Weitbrecht and Jansen, 1985; Wesnes et al., 1987). Our medline search performed in May 20082 yielded more recently published studies (Burns et al., 2006; Cieza et al., 2003; Elsabagh et al., 2005a; Elsabagh et al., 2005b; Mattes and Pawlik, 2004; Mix and Crews, 2000; Mix and Crews, 2002; Stough et al., 2001; Solomon et al., 2002; Santos et al., 2003; Singh et al., 2004). 40 of 57 studies were not considered from the Cochrane review3 due to the following reasons: (Schubert and Halama, 1993) assessed acute doses, other problems were the lack of appropriate statistical reports (Arrigo, 1986; Arrigo and Cattaneo, 1985; Mancini et al., 1993; Maurer et al., 1997) and lack of domain-specific objective tests (Augustin, 1976; Bru¨chert et al., 1991; Chartres et al., 1987; Eckmann, 1990; Eckmann and Schlag, 1982; Haase et al., 1996; Halama et al., 1988; Kade and Miller, 1993; Kanowski et al., 1996; Le Bars et al., 1997; Mazza et al., 2006; Napryeyenko and Borzenko, 2007; Pidoux et al., 1983; Schmidt et al., 1991; Schneider et al., 2005; Taillandier et al., 1986). Four other studies were not considered as they only provided physiological data (Ko¨ltringer et al., 1995; Schulz et al., 1991; Schultz, 2002; Semlitsch et al., 1995). Lack of randomization was the problem of Heinen et al. (2005), Israel et al. (1977), Moreau (1975) and Teigeler and Pieprzyk (1994). There was no placebo group in other studies (Ercoli et al., 2003; Erdincler et al., 1996; Franco et al., 1991; Gerhardt et al., 1990; Gomez, 1997; Haan et al., 1982; Itil and Martorano, 1995; Itil et al., 1998; Vorberg, 1985). We applied similarly rigid methodological criteria to the Cochrane review in selecting ’all relevant, unconfounded, randomized, double-blind controlled studies, in which extracts of Ginkgo biloba at any concentration and over any period of time were compared with placebo’ (Birks et al., 2002; p. 1). In contrast to the 2 Different dates of the Cochrane and the medline search do not raise any problems because the former yielded only older studies whereas the medline search captured recently published papers. 3 Reasons to reject articles were similar for our medline search and thus are given for the sake of space only for the Cochrane review.

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Cochrane review, studies reporting treatment of less than 1 month were excluded. Combinations were not included if they did not allow to separate effects of ginkgo per se (e.g. combination with ginseng, Wesnes et al., 1997, 2000). Trials were included if direct unconfounded comparisons between ginkgo and placebo were possible although a second kind of intervention was assessed (e.g. memory training: Israe¨l et al., 1997; Nicergoline: Gessner, 1985). Objective cognitive performance in standardized psychometric tests is reported in this review, whereas subjective questionnaires and ratings of volunteers, patients or others were rejected. This distinction is also common to other reviews (Oken et al., 1998). Objective psychometric tests differ by their very nature from subjective questionnaires or from subjective rating scales—such as the Hamilton Depression Scale used by physicians. It is misleading if objective psychometric performance tests are summarized under the heading of ‘rating scales’ (Birks and Grimley Evans, 2007; p. 28). Another difference to other reviews is our focus on dependent measures, i.e. the inclusion of studies irrespective of the presence of cognitive impairment. No limitations with respect to age or diagnosis are made. Thus we included trials with healthy subjects and we did not consider most of the studies on dementia. Exclusion of the majority of dementia-trails was due to methodological reasons, i.e. because they only report global cognitive outcome measures. If a measure consisted of two distinguishable parameters attributable to specific functions, the trial was included. If more than two cognitive functions were summarized by the sum score of the respective test—as in the example of the Syndrom-Kurz-Test above—this constituted a ‘global measure’ and the test was excluded from analysis. If a trial reported at least one specific-function measure although also citing one or more global measures, the specific measure was included (e.g. Halama, 1991). Similar to this criterion, some randomized controlled-group trials had to be excluded if interpretation of data was difficult. For example Vesper and Ha¨nsgen (1994) evaluated 120 mg of Lichtwer’s LI 1370 extract (25%/6%) in 86 outpatients (mean age ¼ 62.7 years) suffering from ‘cerebral insufficiency’ for 12 weeks and used standardized and normative psychometric tests. Unfortunately, the way these tests and respective dependent variables are described do not allow allocation of performance to specific cognitive functions. More serious is the methodological flaw of this trial that no adequate statistics are reported to compare the ginkgo versus placebo group after 12 weeks. Similarly, superiority of Ginkgo in a 12-weeks RCT Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

ginkgo biloba: neuropsychological effects of chronic administration

over placebo is evident in an attention/memory-test, but no statistical results are reported (Halama et al., 1988). Thus, even well designed studies had to be rejected from entering this review if the description of outcome measures, results and statistics were not adequate or not specific enough to answer our question on dissociable functions. Pure sensory measures—also often lacking these psychometric prerequisites—and measuring more basic functions for example the threshold for detection of simple stimuli were not considered (e.g. flicker fusion frequency; Gessner et al., 1985). The same applies to tests heavily loading on a motor-factor (e.g. pursuit rotor tracking; Gessner et al., 1985). As stated above, in contrast to other reviews, studies reporting global cognitive measures are not reported as they do not answer the question of specificity. In order to reduce a-errors due to multiple comparisons and for reasons of clarity if different treatment durations are reported, the largest time interval was chosen for this review. Therefore, one trial enters this review only with one data set, i.e. its results from the highest dose and the longest treatment duration, while neglecting other findings from the same RCT. For example, in the study of van Dongen et al. (2000), 160 and 240 mg were used, and after 12 weeks, Ss of the ginkgo group were randomized once again to either continue ginkgo or placebo. Thus, for this review, only objective test results after 240 mg and 24 weeks (vs. placebo) are reported. Using only one data set per trial avoids possible biases due to correlated data. As a consequence, neuropsychological effects are collected independently from different trials, although the database is becoming more narrow following this rationale. The one data set per trial rule was also applied to reports about subgroups: only direct comparisons between total groups are reported—sub-group analyses apart from age are not considered4. Only significant differences ( p < 0.05) using adequate statistical procedures are reported. The citation of improved cases per sample is not sufficient although other aspects of a trial might yield a perfect JADAD score (e.g. Augustin, 1976). Also due to reasons of clarity, not the intention-to-treat analysis results but the smaller samples for completers (per protocol set) enter this analysis—similar to the first 4 There may be conflicting results before and after the inclusion of control variables. This scenario was avoided as only studies reporting adequate statistics were selected. For example, if baseline differences between groups or other factors violating internal validity were not controlled, then this trial was abandoned. If control variables entered the final analysis, then only these results were considered. For example, Mancini et al. (1993) report significant superiority of ginkgo, but this was rejected because baselinedifferences were not controlled by an analysis of covariance.

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Cochrane review (Birks et al., 2002). Typically there is an equal amount of adverse effects and dropouts in both groups—at least in studies on cognitively impaired individuals (Birks and Grimley Evans, 2007). Considering the analysis without the ‘white noise of dropouts’ seemed more adequate in order to identify sensitive cognitive outcome measures. As an exception, studies in which compliance was carefully checked but only the intention-to-treat sample is described are still included, although it is not clear how this differs from the final per protocol set (e.g. Elsabagh et al., 2005a). Instead of omitting the whole trial from our review, the number of volunteers enrolled into the trial is used as an estimate. Extraction and adequate description of critical variables from selected studies Taxonomy of cognitive functions. Table 1 gives a brief summary of the descriptive taxonomy used here (cf. Solso, 2001). In the domain of memory, we relied upon the well established distinction between short- and long-term memory specified by a working memory model (Baddeley and Hitch, 1974). Attentional subsystems are in accordance with the popular framework of Posner (1992), stressing intensity versus selectivity sub-functions. Concerning intelligence, the distinction between crystallized and fluid functions seemed central. Contrary to other domains (memory, attention, intelligence), there is no well-accepted comprehensive model of executive sub-functions (Solso, 2001). Therefore, in this domain several crucial aspects are listed. For reasons of clarity, Table 1 is restricted to cognitive sub-functions including examples of tests for each sub-function. This taxonomy resembles other reviews (Burns et al., 2006; Crews et al., 2005). Different psychometric tests reflecting the performance in a specific function will be presented in the table of results, i.e. in the framework of studies summarizing chronic effects of ginkgo (Table 2). In order to avoid over-sophistication, some functions were summarized although neuropsychologists may argue that they are somewhat different—e.g. vigilance being defined as monotonous and long-lasting detection of seldomly occuring targets is summarized under the heading of sustained attention. Working memory results in ginkgo trials assessed mainly the executive component and not the role of its so called slave systems underlying more passive short-term storage, therefore working memory is summarized under the heading of executive functions. As Table 1 indicates, we tried to omit pseudoexplanatory terms—such as ‘frontal functions’ (e.g. Crews et al., 2005). Such terms might shadow any Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

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Table 1. Cognitive functions assessed in studies using Ginkgo biloba preparations Ccognitive function Memory Short-term memory Verbal short-term memory Visual short-term memory Long-term memory Verbal long-term memory Visual long-term memory Attention Intensity aspect Alertness Speed Selectivity aspect Selective attention Divided attention Executive functions Working memory Concept formation Planning Flexibility Intelligence Crystallized Fluid

Description

Example(s) of test(s)

Rehearsal and maintainance of verbal information Rehearsal and maintainance of non-verbal information

Digit span forward; word list immediate Block span forward; pattern recognition

Recall/recognition of verbal information after minutes/distraction Recall/recognition of visual information after minutes/distraction

Recall story after 30 min Visual reproduction delayed

Basic physiological alertness over hours (arousal), alertness incl. vigilance (monotoneous) Speed of information processing (short-time and just one focus)

Simple reaction time over time Sustained attention tests Trail making A

Focusing certain information while ignoring other aspects/sources Focusing on two kinds of information/sources simultaneously

Choice reaction time; cancellation tests Dual tasking sub-tests

Manipulation of information currently maintained in short-term memory Identification of underlying structure or principle, e.g. category Goal-formation, anticipation, feedback-utilization in non-routine tasks Switching focus between different aspects or tasks

Digits backward Card sorting test Stockings of Cambridge Trail making B; digit-symbol

Semantic knowledge; largely depending on language, education and social background Dealing with new demands; less depending on language, etc.

Vocabulary; comprehension; similiarities

specific effects—similarly to global cognitive measures criticized above. One methodological problem still persists despite our focus on functionspecific psychometric measures: even modern, up-to date psychometric tests deliberately tap different cognitive processes, thus complicating the adequate labelling of cognitive subfunctions. In line with our aim to detect effects on specific and empirically dissociable cognitive sub-functions, the construct-validity of tests and a neuropsychological task-analysis were performed. For example, if digit span forward and backward are reported separately, changes in the first are summarized under the heading of ‘verbal short-term memory’ reflecting functioning of the slave system (phonological loop). In contrast, changes in the backward span will be attributed to ‘working memory’ as it additionally demands some central executive processing. As it demands not just rehearsal in the phonological loop but active manipulation of the material in order to spell the number backward correctly. This detailed description is not possible if a digit span or another test result is reported using a comprised measure (i.e. digits forward and backward). We admit that also some other psychometric parameters are confounded in terms of the cognitive functions which are involved in solving a specific task. For example, the recall of a prose passage is often used as an episodic learning task (logical memory, e.g. part of the Wechsler Memory Scale; Wechsler, 1945). The immediate free recall taps short-term verbal memory as Copyright # 2009 John Wiley & Sons, Ltd.

Block design; fluency; object assembly

especially the last of the orally presented words of the prose passage may be rehearsed in the phonological loop. On the other hand, the duration of this immediate free recall may exceed the duration of time and the specific processes of short-term (or verbal working) memory, thus tapping some aspects of long-term memory. Despite this problem, immediate recall of a story, a word list even extending the short-term store (i.e. supra-span) was attributed to short-term memory whereas their delayed recall could be more clearly conceptualized as operationalization of long-term memory. Conversely, in the search for adequate terms we had to be careful not to become over-specified, because otherwise any grouping of results and our search for coherent patterns of change after ginkgo-administration would become impossible. Therefore, we skipped the distinction between verbal and non-verbal working memory: similar to the example of vigilance (see above), we had to summarize some functions if they did not yield enough data. For the same reason, simply ‘verbal working memory’ will be used as the heading for results of the Paced Auditory Serial Addition Task (PASAT). In this test, digits are given auditorily at a specific rate and the subject has to add only the two recently presented numbers and give the result consecutively in an oral manner. Therefore, numbers presented and responses given earlier have to be suppressed. When summarizing this demand under the heading of ‘working memory’ we try to omit overHum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

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ginkgo biloba: neuropsychological effects of chronic administration Table 2. Chronic effects of Ginkgo biloba: randomized placebo-controlled double-blind trials RCT duration— daily dose

Outcome measures— improveda

38 Ss with dementia of Alzheimer type 60–80 years (mean 72 years)

120 mg of EGb 761 extract for 12 weeks

Alertness Simple reaction time Flexibility Digit symbol substitution Verbal short-term memory Digit span

Gessner (1985)

60 Ss with ‘symptoms of cerebral deterioration’ 57–77 years (mean 66 years)

120 mg of EGb761 for 12 weeks

Wesnes et al. (1987 )

54 Ss with ‘mild idiopathic cognitive impairment’ 62–85 years (mean 71 years)

120 mg of EGb761 for 12 weeks

Reference

Sample size—age

Weitbrecht and Jansen (1985)

Selective attention Number matching task correct reactions (accuracy)

Verbal short-term memory Word recognition speed

Hartmann and Frick, 1991

52 Ss with vascular dementia 40–80 years (mean 63 years)

150 mg of Lichtwer’s Li1370 extract (25%/6%) for 12 weeks

Rai et al. (1991 )

31 Ss with ‘mild to moderate memory impairment´ 54–89 years (mean 76 years)

120 mg of EGb 761 for 24 weeks

Halama (1991)

42 Ss with ‘early’ degenerative or vascular dementia 35–85 years (mean 61 years)

150 mg of Lichtwer’s Li1370 extract (25%/6%) for 12 week

Bru¨chert et al. (1991)

209 Ss with ‘organic brain syndrome’ 45–80 years (mean 69 years)

150 mg of Lichtwer’s Li1370 extract (25%/6%) for 12 weeks

Selective attention Classification task median reaction time flexibility Kendrick digit copying task Verbal short-term memory Digit recall task magnitude of error number correct before first error Visual short- term memory Kendrick object learning task Speed Trail making A

Outcome measures—not improvedb

Alertness Simple reaction time Pauli test Selective attention Vienna determination test choice reaction time (median, milliseconds) speed (number of signs) errors (omissions and false alarms) Selective attention Number matching task reaction time (speed) Choice reaction takes reaction time accuracy of reactions Speed Speed in detection—reaction time accuracy in detection of targets Flexibility Digit symbol substitution Verbal short-term memory Digit span forward Verbal long-term memory word recognition accuracy word recall Visual short-term memory Benton visual reproduction test Working memory digit span backward speed Trail making A Verbal short-term memory Gru¨nenberger memory test Selective attention Classification task mean reaction time number attempted

Verbal short- term memory Digit recall task total number of correct

Speed Trail making A

(Continues)

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Table 2. (Continued) RCT duration— daily dose

Outcome measures— improveda

36 Ss with ‘organic brain syndrome’ 53–69 years (mean 63 years)

120 mg of EGb761 for 8 weeks

Hofferberth (1991)

24 Ss with ‘cerebro-vascular risks’ 62–74 years (mean 68 years)

120 mg of EGb761 for 12 weeks

Gra¨ßel (1992)

53 Ss with ‘cerebral insufficiency’ 21 (MMSE mean 26.1) 55–86 years (mean 69 years)

1.14 mg flavone glyco sides/1.93 ginkgolides per day (ethanolic extract) for 24 weeks

Mix and Crews (2000)

40 healthy Ss 55–86 years (mean 68 years) (MMSE > 23)

180 mg of EGb761 extract for 6 weeks

Reference

Sample size—age

Hofferberth (1989)

Outcome measures—not improvedb

Speed/flexibility Cerebral screening test (CI-Test) Selective attention Vienna determination test Minimal difficulty Medium difficulty Maximum difficulty Short-term memory Factor of Israel’s test battery Fluid intelligence Fluency factor of Israel’s battery Planning Porteus maze (milliseconds) (no. of responders) Visual short-term memory Benton visual reproduction test

Speed Colour naming of Stroop Test Trail making A

Long-term memory Factor learning of Israel’s battery

Speed Trail making A Flexibility Digit symbol substitution Verbal short-term memory/ speed Expanded mental control test Verbal short-term memory Word list recall verbal long-term memory Word list recognition Speed Word naming of Stroop Test Selective attention Interference task of Stroop test Flexibility Trail making B Verbal short-/long-term memory Logical memory (immediate/delayed) Visual short-/long-term memory Visual reproduction (immediate/delayed) (Continues)

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ginkgo biloba: neuropsychological effects of chronic administration Table 2. (Continued) RCT duration— daily dose

Reference

Sample size—age

van Dongen et al. (2000)

214 Ss with age-associated memory impairment; vascular, mixed or Alzheimers´ dementia >50 years (mean 83 years) (range not given)

240 mg of EGb761 for 24 weeks

Stough et al. (2001)

50 healthy Ss 18–40 years (mean 30 years)

120 mg of Blackmore’s Gb extract (24%/6%) for 30 days

Solomon et al. (2002)

203 healthy Ss (MMSE > 26) 60–82 years (mean 69)

120 mg of Ginkoba Gb extract (24%/6%) for 6 weeks

Mix and Crews (2002)

240 healthy Ss >60 years (mean 67 years) (range not given)

180 mg of EGb761 extract for 6 weeks

Outcome measures— improveda

Working memory Working memory speed Digit span backward Verbal long-term memory Word list recall delayed Selective attention Inspection time (go-nogo task)

Verbal long-term memory Word list (selective reminding) delayed free recall delayed recognition Visual long-term memory Long-term recognition of faces Flexibility Digit symbol substitution Fluid intelligence Block design

Outcome measures—not improvedb Speed Trail making A Verbal short-term/working memory Digit span (forward plus backward) Verbal short-/long-term memory Word list learning (sum of:) immediate recall delayed recognition Verbal short-term memory Digit span forward

Alertness Simple reaction time Flexibility Digit symbol substitution Speed Trail making A Selective attention Stroop colour word task Speed Mental control Flexibility Digit symbol substitution Verbal short- term memory Digit span Logical memory immediate Word list learning (trials 1–5) verbal long- term memory Logical memory delayed Word list learning (short delay recall) Word list learning (long delay recall) Word list learning (long term recognition) Visual short-term memory Visual reproduction immediate Visual long-term memory Visual reproduction delayed Fluid intelligence Boston naming test Controlled category fluency Verbal short-term memory Word list (selective reminding) immediate free recall short term recall Verbal long-term memory Word list (selective reminding) long-term storage consistent long-term retrieval

(Continues)

Copyright # 2009 John Wiley & Sons, Ltd.

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Table 2. (Continued) Reference

Sample size—age

RCT duration— daily dose

Outcome measures— improveda

Outcome measures—not improvedb

Santos et al. (2003)

48 male healthy Ss except ‘complaints of mild loss of memory’

80 mg Maze Produtos Gb extract (24%/6%) for 8 months

Visual short-term memory Block span forward Working memory Block span backward Speed Mental control errors speed Visual long-term memory Recall Rey figure (delayed) Verbal long-term memory Delayed recall word list intrusion errors perseverations repetition errors Verbal short-term memory Logical memory (immediate recall) Word pairs (unrelated)

Verbal short-term memory Digit span forward Working memory Digit span backward

MMSE>23 (MMSE mean 27.2) 60–70 years (mean)

Cieza et al. (2003)

66 healthy Ss 50–65 years (mean 56 years)

240 mg of EGb761 for 4 weeks

Selective attention Cancellation test speed accuracy Flexibility Digit symbol substitution Crystallized intelligence Vocabulary Comprehension Similarities Fluid intelligence Block design Object assembly Arithmetics Concept formation/flexibility Card sorting test non-perseverative errors perseverative errors Selective attention Choice reaction movement time Alertness tapping speed (3/4 variables)

Singh et al. (2004)

60 healthy Ss 21–39 years (mean 28 years)

80 mg standardized Gb extract (not specified) for 6 weeks

Short-term verbal memory Phone number recall 10 numbers with interference

Visual short-term memory Recall Rey figure (immediate) Verbal long-term memory Delayed recall word list number correct Verbal long-term memory Logical memory (delayed recall) Verbal short-term memory Word pairs (semantically related)

Fluid intelligence Copying Rey figure Picture completion Picture arrangement Concept formation/flexibility Card sorting test trials per category Selective attention Choice reaction release time Colour word test Speed Trail making A Verbal memory (short-/long-term) Word list (recall/recognition) Long-term verbal memory Incidental learning Short-term verbal memory Phone number recall 10 numbers without interference 7 numbers without interference 7 numbers with interference Short-term visual/-verbal memory Name recall (based on face) First last name match and recall Short-term visual memory Facial recognition (Continues)

Copyright # 2009 John Wiley & Sons, Ltd.

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ginkgo biloba: neuropsychological effects of chronic administration Table 2. (Continued) Reference

Sample size—age

Mattes and Pawlik (2004)

39 healthy Ss 18–40 years (mean 24 years)

Elsabagh et al. (2005a)

40 healthy Ss 18–26 years (mean 21 years)

Elsabagh et al. (2005b)

81 females postmenopausal Stages 1 þ 2 51–67 years (mean 58 years)

RCT duration— daily dose 184.5 mg (mean) standardized Gb extract (24%/6%) (no EGb 761) for 13 weeks 120 mg of Lichtwer´s Li1370 extract (25%/6%) for 6 weeks

120 mg of Lichtwer’s Li1370 extract (25%/6%) for 12 weeks

Outcome measures— improveda

Outcome measures—not improvedb Alertness Vigilance (1 h after lunch)

Working memory Placed auditory serial addition items correct in the two fastest trials Spatial working memory (boxes) within errors between errors strategy Short-term visual memory Pattern recognition latency errors Spatial recognition latency errors Long-term verbal memory Delayed recall of words Long-term visual memory Delayed recall of pictures Planning Stockings of Cambridge initial thinking time 4 move-problem initial thinking time 5 move-problem time per moves 4 move-problem time per moves 5 move-problem Flexibility Intra-/extra-dimensional shift stages completed errors before extradimensional shift errors at extradimensional shift Working memory Paced auditory serial addition items correct 2 fastest trials Delayed matching to sample total correct latency Short-/long-term verbal memory Logical memory (immediate/delayed recall) Long-term visual memory Picture recall Planning Stockings of Cambridge initial thinking time 4 move-problem initial thinking time 5 move-problem time per moves 4 move-problem time per moves 5 move-problem Flexibility Intra-/extra-dimensional shift trials needed errors (Continues)

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Table 2. (Continued) RCT duration— daily dose

Outcome measures— improveda

Outcome measures—not improvedb

38 Ss with multiple sclerosis 18–60 years (mean 49 years)

120 mg of ginkgo extract (31, 4% flavonol-glycosides 4,5% terpenoides) 12 weeks

Selective attention Interference task of Stroop test

Burns et al. (2006)

80 healthy Ss 55–79 years (mean 62 years) 1st sample (elderly healthy)

120 mg Blackmore´ Ginkgoforte extract (24%/6%) for 12 weeks

visual-verbal long-term memory (mean of:) Visual auditory Memory for names

Burns et al. (2006)

104 male healthy Ss 18–43 years (mean 30 years) 2nd sample (young healthy)

120 mg Blackmore´s Ginkgoforte extract (24%/6%) for 12 weeks

Speed Word naming of Stroop Test Colour naming of Stroop Test Flexibility Symbol digit modalities test Fluid intelligence Controlled oral word association Working memory Paced auditory serial addition Divided attention Usual field of view test Verbal long-term memory Word list recall delayed Fluid intelligence (mean of:) Concept formaton Analysis-synthesis Crystallized intelligence (mean of:) Picture vocabulary Oral vocabulary Crystallized intelligence (3rd test) Spot-the-word Short-term memory (mean of:) Memory for sentences Memory for words Working memory Pattern backward masking Speed (mean of:) Visual matching Cross out Speed (3rd test) Inspection time Selective attention Odd-man-out reaction time task decision time movement time Planning Self-ordered pointing Fluid intelligence Reasoning (matrices) Crystallized intelligence Information (semantic knowledge) Verbal short-term memory Digit span Visual short-term memory Picture recognition Verbal long-term memory Memory for names Visual long-term memory Visual auditory Speed Visual matching Flexibility Digit symbol substitution Selective attention

Reference

Sample size—age

Lovera et al. (2006)

(Continues)

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357

Table 2. (Continued) Reference

Sample size—age

RCT duration— daily dose

Outcome measures— improveda

Outcome measures—not improvedb Odd-man-out reaction time task decision time movement time Colour word interference (Stroop) interference score working memory Pattern backward masking Paced auditory serial addition

a

Cognitive function: psychometric test specific task/score. Cognitive function psychometric test specific task/score.

b

specific terms of processes also assessed in this test— e.g. ‘processing speed’ or ‘response inhibition’ which are all of some relevance for adequate performance in this quite demanding task. Similar problems emerged with some IQ-tests: the block design of the popular Wechsler Adult Intelligence Test taps executive aspects apart from its visuospatial demands—still it is summarized in the category of fluid intelligence because traditionally several IQ tests which do not rely heavily on education and language-dependent functions are conceptualized as ‘fluid’ and block-design is not the only one relying heavily on executive processes (Table 2). Because psychometric construct validity and neuropsychological task analysis were major guidelines for grouping, in same category it happened that tests of different format were summarized. For example, performance of the trail making B test in which you have to cross 1-A-2-B3-C-etc. is summarized under the heading of flexibility although it is a bit different from the digit-symbol Wechsler IQ-subtest also summarized under this label. At least it shares the major component of switching deliberately between different targets (symbols or numbers). If one sub-test gives just one score, then the sub-function assessed in most of its items was chosen, e.g. the ‘Mental control’-sub-test of the Wechsler Memory Scale predominantly taps pure speed, although its third item comprises addition starting with the number 1 in steps of 3 (working memory task). Method of extracting and reporting outcomes on specific cognitive functions Table 2 summarizes extracted data from the selected trials. In addition to the range and mean of the age of the sample, the summary score of the Mini-Mentalstate examination is reported to characterize the amount of cognitive decline (MMSE ¼ 30 perfect Copyright # 2009 John Wiley & Sons, Ltd.

score; Folstein et al., 1975). Distribution of sex is not reported as none of the papers reported differential effects. Education would be interesting to report as it is highly correlated to most of the psychometric variables and, given the lack of age-education-based norms, education would be crucial for their interpretation. Unfortunately, respective data are lacking and thus this variable was excluded. In case of ill-defined diagnostic categories, their label is paraphrased from the original paper, especially because there is a huge number of such terms in the early literature (e.g. ‘organic brain syndrome’; cf. Birks and Grimley Evans, 2007). Unfortunately, this methodological flaw is also seen in the latest publications as they often use the term ‘mild cognitive impairment (MCI)’ without using at least one of the available operational definitions for this pre-dementia condition (Petersen et al., 2001— ‘diagnosis . . . is usually based on assessment using rating scales’ (Birks and Grimley Evans, 2007; p. 2)— despite progress in NMR and other validation tools. In addition to sample characteristics, Table 2 gives the dosage and type of the ginkgo extract used and informs about the largest treatment duration of the respective trial—if there were several endpoints reported. Following other reviews (Canter and Ernst, 2007), the percentages of these two components in each of the extracts are given in Table 2. The last two colums of Table 2 report significant superiority of ginkgo over placebo in the respective trial or lack of such evidence. Results are listed for specific function(s), tests used to measure them and parameters of the test if there were more than one of them within the same test or if the parameter is quite unusual (e.g. percentage of responders; Oswald et al., 1997). As only trials reporting adequate statistics were included, results beyond p < 0.05 are listed as improvements. Even strong trends in favour of ginkgo are summarized only in the last column—i.e. indicating lack of effects. Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

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Differences in preparations used, dosages and duration of treatment There is considerable variation with respect to preparation, dose and duration of treatment. Most of the clinical studies used EGb 761 and other preparations which do not share identical pharmacological properties (Itil and Martorano, 1995)5. Of 29 studies selected for this review, 15 used EGb 761 and 5 studies reported use of Lichtwer’s LI 1370 extract (Bru¨chert et al., 1991; Elsabagh et al., 2005a,b; Halama, 1991; Hartmann and Frick, 1991). LI 1370 is similar to EGb 761 in respect to elimination of harmful compounds and standardization to 25% ginkgo-flavone glycosides and 6% terpene lactones. Although studies assessing bioequivalence are missing, a number of other preparations provide the same ratio of 24% flavone and 6% terpene constituents (Blackmore’s extract: Burns et al., 2006; Stough et al., 2001; Ginkoba: Solomon et al., 2002; Maze Produtos: Santos et al., 2003; no-name: Mattes and Pawlik, 2004). This ratio is not reported in the remaining studies (unspecified formulas: Brautigam et al., 1998; Lovera et al., 2007; Stough et al., 2001). For the 15 studies using EGb 761 MCI was the main focus (n ¼ 8), whereas studies on dementia (N ¼ 3) and healthy controls were rare (n ¼ 3). This is contrasted by the 14 studies using other preparations: most of them were based on healthy controls (n ¼ 8), less attention was given to MCI (three studies) and dementia (n ¼ 2). One study treated depressed patients using EGb 761 (Schubert and Halama, 1993) and another used an unspecified formula in multiple sclerosis (Lovera et al., 2007). Significant changes emerged in 67% of the psychometric comparisons in demented patients using EGb 761 (n ¼ 3) and in 50% if other extracts were administered (n ¼ 2). In MCI patients, the respective numbers were 60% using EGb 761 (n ¼ 8) versus 63% for other extracts (n ¼ 3). Fourty one per cent of cognitive parameters significantly improved in healthy subjects if EGb 761 was applied (n ¼ 3) but this was the case for only 16% of comparisons if other preparations were used (n ¼ 8). These extremely different and small numbers of studies per condition using EGb 761 or not ask for cautious interpretations. Apart from this question of preparation dosage and duration of treatment might influence our results. In order to tackle this issue, correlations of dosage, duration and their cumulative effect (dosage  duraduration) were calculated using all 29 studies included 5

One of the reviewers suggested to take this crucial topic into consideration.

Copyright # 2009 John Wiley & Sons, Ltd.

in this review. The percentage of significant superiority over placebo does not correlate with dosage of ginkgo (mg/die: r ¼ 0.02; p > 0.10), duration of treatment (weeks: 0.17; p > 0.10) or their cumulative effect (dosage  duration: r ¼ 0.16; p > 0.10). After exclusion of RCTs dealing with healthy subjects, 18 studies remained and the same lack of relationships with dosage, duration and dosage  duration is obtained (all r < 0.06; all p > 0.10). Taken together, studies included in this review are heterogeneous with respect to diagnoses, ginkgo preparations, dosage and duration of treatment. We found no evidence that the ratio of psychometric functions improved by ginkgo is a function of these6. Therefore, these variables should not necessarily be reconsidered in our search for specific cognitive effects in the following statistical section. Furthermore, given the lack of such general relationships between type, dosage and duration of ginkgo treatment and psychometric improvement, the search for specific cognitive functions specifically sensitive to ginkgo seems even more valuable.

Rationale and method of evaluation of outcomes on specific cognitive functions Table 3 summarizes the evaluation of outcomes on specific cognitive functions using all data from Table 2. The rationale for this evaluation of function-specific effects of ginkgo in trials with more than 1 month of duration followed the rationale behind inferential statistics. The basic assumption is that authors of published studies were blind to the function-specific rationale presented here—making a specific bias practically unlikely: there was no reason to assume that an author prefers to report a significant result for one function while ignoring another. Thus, the Bonferroni rationale of correcting for multiple comparisons which is often lacking in this field (Canter and Ernst, 2007) was applied across all trials included into this review. Bonferroni corrections for multiple comparisons were done within each of the cognitive functions: given one score per test and p < 0.05 as significance level, only 5.0 of 100 tests would become significant just by chance. Therefore, we calculated the percentage of tests per function which became significant related to 6 The lack of relationships found for the studies included in this review does not allow us to give recommendations concerning a specific ginkgo preparation for diagnostic groups in pre-defined dosages for a certain amount of time, although such a clinical ramification was suggested by one of the reviewers.

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ginkgo biloba: neuropsychological effects of chronic administration Table 3. Ratio and percentage of significant effects per cognitive function in chronic treatment RCT’s using Ginkgo biloba Ratio sig./ns Memory Short term memory Verbal short-term memory Visual short-term memory Long-term memory Verbal long-term memory Visual long-term memory Attention Intensity aspect (Alertness Speed Selectivity aspect Selective attention (Divided attention Executive functions Working memory (Concept formation Planning Flexibility Intelligence (Crystallized Fluid

Step 1a % sig. Bonfer-roni (%)

Step 2b Ratio sig./ns % sig.

Ratio sig./ns

Step 3c % sig. Bonfer roni (%)

8.5/26 3/11

24.6 21.4

23.0 20.7

8/17 3/9

32.0 25.0

6.75/16.25 3/7

29.3 30.0

28.1 29.5

6.5/17 2.5/5

27.7 33.0

26.5 32.6

6/17 2/4

26.1 33.3

5/10 2/4

33.3 33.3

32.5 33.0

2/4 7.5/15

33.3 33.3

33.0 33.0

2/4 7/14

33.3 33.3

1.75/3.25 6/12

35.0 33.3

34.8) 33.0

16/17 0/1)

48.5

46.1

16/17

48.5

8.5/10.5

44.7

43.7

3/15.5 2/1 1/9 4/12.5

16.2 66.6 10.0 24.2

15.3 66.4 9.5 23.4

3/15 2/1 1/9 4/12

16.7 66.6 10.0 25.0

3/11 1/1 1/2 3/9

21.4 50.0 33.3 25.0

20.7 49.9) 33.2 24.4

3/3 5/8

50.0 38.5

47.7 37.8

3/3 5/8

50.0 38.5

3/3 5/8

50.0 38.5

47.7) 37.8

Results not in parentheses: more than seven comparisons in total analysis—reliable results. Results in parentheses: less than seven comparisons in total analysis—results not reliable (small sample size). a Cognitive function: all scores per test incl. mixed-function scores. b Cognitive function: without mixed-function scores. c Cognitive function: without mixed-function scores cognitive function and only one score per test.

this chance level. This was done in several steps, as indicated in the respective columns of Table 3. 1st step of calculations. In order to exploit all the data of Table 2, each parameter per test per function was counted as if it did not stem from the same test. For example, if speed and accuracy stemmed from the same test, both were used as if they were not correlated. If the parameter itself was not reported but if the mean of two parameters (e.g. Burns et al., 2006) or their sum (van Dongen et al., 2000) was, this was counted as if only one parameter entered the analysis (because only the mean was tested for significance). The same rationale was applied to factorial scores for the respective function, although they comprised different tests and parameters not reported separately (Israe¨l et al., 1995). Sum- or factorial scores were not reported if fine-graded tests scores underlying them were available. On the other hand, in order to avoid loss of power and reliability right at the beginning of our analysis, mixed categories were still accepted if a result did not tap more than two functions and the singlefunction scores were not reported (as described above). For example, the study of Winther et al. (1998) had to be excluded because more than two functions were summarized: the non-revised Wechsler Memory Scale taps visual and verbal short term memory and speed as Copyright # 2009 John Wiley & Sons, Ltd.

distinct functions and the authors only reported a global score of this test. The same is true for Israe¨l et al.,’s (1995) short- and long-term memory factor as immediate and delayed recollection for both verbal and visual material were included (four distinct subfunctions are confounded; see Table 1). The first column of Table 3 gives the number of significant versus non-significant results in terms of superiority for ginkgo (‘ratio significant/non-significant’; e.g. 3/11 for visual short-term memory). This was done in a conservative manner—although most studies reported two-tailed testing only p < 0.05 improvement in favour of ginkgo was termed ‘significant’. The distinction between studies, cognitive functions, tests and placebo-drug comparisons reported for different test-parameters is crucial: note that there are not 14 studies which assessed visual short-term memory but there were 3 significant and 11 non-significant placebodrug comparisons for psychometric parameters which represent visual short-term memory. Therefore, the first column of Table 3 depicts the number of statistical comparisons for test-parameters which can be summarized under the heading of the respective cognitive function. These comparisons per functio stem from a different amount of studies and it was not unusual that one study or one test contributed more than one placebo-drug comparison to the respective ratio of Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

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significant versus non-significant results. If some parameters of a specific function—let us take ‘speed’ as an example—led to ambiguous results within the same study, they were weighted in column 1 of Table 3 as if they stemmed from different studies. For example, colour naming of Stroop Test and Trail Making A were significant in the study of Mix and Crews (2000) whereas word naming as another parameter for speed was not. The two positive results each earned one point contributing to the sum of ‘significant’ comparisons whereas the negative result is counted as one point in the opposite direction. Thus, given these contradicting results for speed within the same study in three parameters from two tests (Stroop and trails A), the speed parameter from this study does not enter the analysis with 0.5 for significant and non-significant, but with 2 points in favour of significant and one point for nonsignificant. Again in the first column of Table 3, the decimal of 0.5 stems from the finding that one test parameter tackled two cognitive functions. For example, non-significant effects in the cerebral screening test which measures speed but also flexibility in the study of Schubert and Halama (1993) contributed with 0.5 to the non-significant sum of comparisons of speed (1st column, Table 3) and 0.5 to the respective ratio of flexibility as a cognitive sub-function. Given these ratios of significant versus non-significant comparisons of test parameters for each cognitive function, the second column of Table 3 gives the respective percentage of this ratio in terms of significant improvements after ginkgo (‘% significant’). Here, the total number of statistical comparisons per function acts as the frame of reference (¼100%). Then a Bonferroni correction is applied: as 5 of 100 comparisons will be significant by chance given p < 0.05, the third column subtracts from this percentage the by-chance-probability of significance—following the Bonferroni rationale (Table 3: column ‘Bonferroni’).

3rd step of calculations. A third step further accounted for correlations between different parameters from one test by using only one of the scores per test for further calculations. For example, if more than one score was reported measuring planning ability by the Stockings of Cambridge (Elsabagh et al., 2005a,b), only one of these parameters was left for the third step of the analysis. Thus, for example, the number of nonsignificant comparisons of ginkgo versus placebo in the domain of planning dropped from 9 to 2 (Table 3: step 1 and 2 (left and middle) versus step 3 (right part)). Thus, if all improved scores derived from the same test, only one score is left from this test which was added to the summary for this function by a weight of 1.0. If results from the same tests were contradictory, e.g. speed improved but not accuracy, then a 0.5-weight was given to this parameter in the column for significant and another 0.5-weight in the column for non-significant results. The respective weight was only 0.5 if accuracy did not improve in the same test and no other score from this test was reported. In the case of more than two contradictory scores per test, the same logic was applied. For example, Cieza et al. (2003) found significant improvements in three of the four variables of tapping speed, thus a weight of 0.75 is given for significant improvements and a weight of 0.25 for nonsignificant changes in the function of alertness. At this stage of analysis, it was still possible that more than one score from the same study contributed to a specific function—but only if they were stochastically independent because they originated from two different psychometric tests used in the same study. The right part of table gives the corresponding results following the scheme from the other steps—i.e. ratio, percentage of significant results uncorrected for number of comparisons and corrected in this respect (Bonferroni). RESULTS

2nd step of calculations. In the middle of Table 3, results are listed which were obtained following the same algorithm but after exclusion of mixed function scores. Calculations were repeated after exclusion of all measures which were not clearly function-specific, thus not considering any more a result which combined two functions—for example digit span forward and backward, logical memory immediate and delayed and so forth. Any case in which a mixed-measure of two functions was reported was excluded at this stage. Similar to the first step, the ratio of significant to nonsignificant comparisons and the corresponding percentage of significant results is given (Bonferronicorrection is omitted at this step for reasons of clarity). Copyright # 2009 John Wiley & Sons, Ltd.

Evaluation of trials reporting specific cognitive improvements First of all, there is a large heterogenity in the relationships between significant and non-significant results across studies, ages and diagnoses. Even when using comparable samples—elderly without clear deterioration as indicated by the MMSE—quite different patterns emerge. For example, Solomon et al. (2002) found no effects despite using a broad array of cognitive tests, whereas Santos et al. (2003) reported significant superiority of ginkgo in similar tests. The second finding relates to a discrepancy between the proposed taxonomy of cognitive functions using Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

ginkgo biloba: neuropsychological effects of chronic administration

well accepted current models from cognitive and neuropsychological (Table 1) and empirical results on these specific sub-functions (Table 2). Not all functions described in the taxonomy received an equal amount of attention: whereas memory performance often appeared in the list of results (Table 2), attentional, executive and intelligence sub-functions were less thoroughly assessed. This impression skipping through Tables 1 and 2 is quantified by numbers of comparisons reported in the first column of Table 3: there were 79.5 psychometric test parameters from the four memory sub-functions (step 1, Table 3) tested for significance and there is a relative lack of data on visual as compared to verbal and long- compared to short-term-memory results (Tables 2 and 3). Compared to memory as cognitive domain, attention received less interest in terms of frequency of statistical comparisons (62.5 scores providing comparisons of ginkgo vs. placebo; step 1, Table 3). Divided attention was assessed only in one of the studies and alertness which comprises basic measures such as simple reaction time was examined only in six comparisons. Executive scores were tested for significance 48 times, and within this domain researchers were interested especially in working memory (18.5) and flexibility (16.5), less in planning (10.0) and concept formation (3.0 tests). Changes in crystallized mental ability were tested six times, for fluid intelligence more than twice as many were reported (13.0 tests). We chose an arbitrary cut-off of more than seven tests per cognitive subfunction which should be available in order to proceed with summarizing results (which is illustrated by boldtyping and parentheses in Table 3). After correcting for these quite different numbers of comparisons (Bonferroni), in the area of memory 20.7– 32.6% of comparisons still were significant, i.e. 4–6 times more than just by chance. These numbers rose in all four memory sub-functions after exclusion of functionally mixed scores (2nd step of calculation: middle colums of Table 3) and showed highest proportions of significant results if additionally only one score per test was allowed (3rd step of calculation: right portion of Table 3). Significant superiority of ginkgo occurs more often in the delayed (long-term) recollection as opposed to the immediate (short-term) recall of verbal (23.0 short- vs. 26.5% long-term) and visual (20.7% short- vs. 32.6 long-term) material. In the area of attention, the intensity function of speed yielded 33.0%, the selectivity aspect 46.1% significant tests in favour of ginkgo (Bonferroni corrected; left column Table 3). After taking mixed functions and correlated scores from the same tests into account, these figures were reduced only marginally (to 33.0% for speed and 43.7% for selective attention). Copyright # 2009 John Wiley & Sons, Ltd.

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These proportions indicate seven and eight times more significant results than just by chance. Executive functions also showed some sensitivity, as 15.3–20.7% of working memory and 23.4–24.4% of flexibility scores yielded significant results (first and third step of calculation, respectively). Planning was assessed in highly correlated measures and this was restricted to a small number of studies—making interpretations difficult as only 3 scores are left after correction for this kind of possible confounding (3rd step of calculation: right column Table 3). Only 12 fluid intelligence scores were tested for significant change—thus the amount of 37.8% significant results also relies upon a small sample.

DISCUSSION Despite well documented pre-clinical findings of Ginkgo biloba extract, reviews on its clinical application in healthy, cognitively impaired or demented subjects are rather heterogeneous—especially concerning their conclusion about its efficacy (Birks and Grimley Evans, 2007). This paper aimed to disentangle some of these discrepancies by a closer look on psychometric tests and corresponding cognitive sub-functions. Similar to other reviews, even studies using healthy subjects seemed ‘of interest because they may indicate which aspects of cognitive function are affected by Ginkgo biloba and shed light upon underlying mechanisms’ (Canter and Ernst, 2007; p. 266). Another motivation for this review was the impression that over the years the methodology of ginkgo trials improved except for psychometric quality. Progress is evident in the pharmacological description of RCTs which are fitting well to relevant guidelines (Gagnier et al., 2006). Methodology also improved regarding randomization and allocation of subjects (Birks and Grimley Evans, 2007) as indicated by JADAD scores (Jadad et al., 1996) of recent trials (Canter and Ernst, 2007). Similar methodological improvements were not achieved in respect to psychometric tests as they are sparsely characterized in original papers, not thoroughly analysed in existing reviews and psychometric standards are not rigorously applied. For these reasons, we reviewed 29 studies yielding 209 placebo-drug comparisons of psychometric scores in four different cognitive domains comprising 14 subfunctions. After controls for multiple comparisons within each sub-function and of possible relationships between different parameters within the same test, different numbers of comparisons tested for significance are left: 54 tests for memory scores, 42 for Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

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attention, 31 for executive functions and 19 in the domain of intelligence. More surprising is the finding that some sub-functions received little attention (divided attention 1, alertness 5, concept formation 2 and crystallized intelligence 6 comparisons after respective controls). Even if large test batteries were applied, selection of function-specific tests was not theoretically grounded, leaving a scattered unsystematic pattern of heterogeneous test scores for this review. This pattern may have invited researchers for quite contradictory reviews (see Introduction), as it looks confusing unless a taxonomy of cognitive functions is used. This taxonomy is applied here and it suggests that the lack of crucial functions being tested tends to penalize ginkgo (tendency for b-errors). For example, divided attention has long been known as an early feature of early Alzheimers dementia (Baddeley et al., 1991) but has been examined only once. Instead, simple functions such as digit span forward are often tested although there is little reason why this should improve (b-error; see below). Compared to this taxonomy—memory, attention, executive and intelligence—the search for psychometric effects of ginkgo turns out to be less comprehensive than suggested by long lists of tests given in some reviews, again favouring b-errors (e.g. Birks and Grimley Evans, 2007; Crews et al. 2005). These restrictions make it difficult to identify strengths and weaknesses in terms of functions sensitive to ginkgo. On the other hand, even after controls for multiplecomparisons and correlated scores, different cognitive functions yield large proportions of significant comparisons: 20–48% of placebo-drug comparisons yield superiority of ginkgo. Relying again upon the smallest but best controlled number of comparisons (right column of Table 3) fluid intelligence (37.8%) and selective attention (43.7%) show the highest percentages. Although ginkgo is traditionally associated with amelioration of memory, effects in four different memory sub-functions are a bit smaller (short-termand long-term verbal and short- and long-term visual memory 28.1, 29.5, 32.5 and 33.0%, respectively). Sub-functions from other domains scored in a similar range: executive functioning (planning 33.2%; working memory 20.7%; flexibility 24.4%) and the basal intensity aspect of attention (speed: 33.0%). There are two possible interpretations of this pattern— one for having found a trend towards specificity, the other that methodological problems made it difficult to detect selectivity—no matter whether specificity truly exists or not. Both interpretations are plausible and by no means exclusive. The first interpretation claims specificity as the highest percentages of significant Copyright # 2009 John Wiley & Sons, Ltd.

superiority were found in two quite complex cognitive functions, i.e. fluid intelligence and selective attention. In a more simple sub-function of attention—pure speed—results are less convincing. This is in line with the finding that delayed retrieval from long-term memory is more reliably improved by ginkgo compared to the less demanding and less ageing-sensitive sub-function of short-term memory. This difference holds true irrespective of the kind of material remembered (verbal vs. visual) and is most pronounced if all placebo-drug comparisons are assessed (left column of Table 3). Furthermore, positive effects on different executive parameters (namely flexibility and planning) fit to this interpretation as they rely upon frontal processes sensitive to ageing similar to fluid intelligence, longterm memory and selective attention (cf. MacPherson et al., 2002). This pattern is compatible with subjective ratings indicating clinical significance of change: ratings of alertness were not improved after 2 (Rigney et al., 1999) or 7 days (Hartley et al., 2003) but after 4 months of treatment (sedation, sleep quality, Cockle et al., 2000) and after several weeks in a number of studies (see Soholm 1998 for review). While alertness is improved in these subjective ratings objective measures show larger improvements in more complex aspects of attention (Tables 2 and 3). Whereas this pattern of objective and subjective improvement is compatible but cannot strictly be linked to pre-clinical data on enhancement of EEG, mitochondrial or transmitter-functions (see Introduction), the pattern of objective psychometric improvement found in this review is in accordance with animal studies: it resembles improvement of scopolamine-induced memory defictis in rats (Chopin and Briley, 1992) and of age-correlated memory impairments in mice (Stoll et al., 1996) in a passive avoidance model. It is also compatible with better operant learning of a complex reaction in mice (sequential pushing two levers) and long-term retention of its correct order after 10 weeks (Winter, 1991). Another possible parallel to specificity for complex processes is the amelioration of behavioural adaptation despite adverse environmental conditions, ‘a property that supports its clinical use in treating cognitive impairment, especially in elderly patients’ (Rapin et al., 1994; p. 1009): young and old rats learned to discriminate lights in order to obtain a small amount of drinking water after pressing the correct lever. Auditory stress-induced detrimental changes in learning and plasma cortisol were restored. The second interpretation of our data suggests that methodological problems prohibit detection of specific effects. For example, no reasons are given for selection of psychometric instruments and cognitive functions Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

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despite rather clear suggestions for sensitivity from animal studies. This arbitrary selection of tests in addition to the heterogenity of trials concerning extracts, diagnoses, sample-sizes, treatment durations and methods of statistical analysis make it difficult to draw conclusions. Furthermore, there are many hints in favour of a- and b-errors—both hampering the search for specificity. a-errors comprise a possible publication bias as well as problems with randomization, sample description, multiple comparisons and statistics—tending to overestimate effects. b-errors are less mentioned in other reviews, although they impair the detection of any specificity. They result from violation of psychometric principles, lack of power, practice or ceiling effects and other factors lowering sensitivity.

a errors Bias problems of publication, randomization and selection of samples. Poor or questionable randomization, possibility of a publication bias and insufficient or implausible sample descriptions seriously question the validity of RCTs. Although they may equally enhance the risk of a- and b-errors, they tend to be discussed only as an argument against efficacy of ginkgo. For example, the latest Cochrane review (Birks and Grimley Evans, 2007) states that many of the early studies were small and lacked proper randomization— the rating for its quality is ‘allocation conceilment— unclear’ (Augustin, 1976; Arrigo, 1986; Arrigo and Cattaneo, 1985; Eckmann, 1990; Eckmann and Schlag, 1982; Halama, 1991; Hartmann and Frick, 1991; Hofferberth, 1989, 1991; Oswald et al., 1997; Weitbrecht and Jansen, 1985; Wesnes et al., 1987). Unfortunately, no hints for a publication bias are given. The same is true for the criticism of non-reliable randomization in early trials (lack of computers). Why is a paper–pencil randomization less reliable than an electronic one? Despite the fact that randomization is neither new nor difficult, lack of understanding is assumed—‘the underlying logic of randomization has become more widely understood’ (p. 8)—’it is simply that people did not fully understand the rationale and purpose of the methodology of clinical trials’ (p. 8). To perform an RCT, lege-artis may not necessarily be a problem of early studies: for example, the study of Solomon et al. (2002) was not double-blind, as the placebo looked different and simple finger pressing revealed this difference. The same is true for another recently published study (Santos et al., 2003) where education is stated to be identical for both groups Copyright # 2009 John Wiley & Sons, Ltd.

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although large IQ-differences are evident (adequate randomization?). Multiple testing. Reporting many placebo-drug differences and different treatment durations (e.g. Burns et al., 2006) provokes a-errors if no adjustment is applied: ‘A methodological weakness observed in several of the studies was multiple hypothesis testing, a weakness which cause us to question the validity and significance of single or a few positive outcomes reported among a large number of otherwise negative results’ (Canter and Ernst, 2007; p. 266). Rarely the significance level is divided by the number of comparisons (Bonferroni adjustment). a-errors may occur if the new significance level is arbitrarily set at p < 0.01 (Santos et al., 2003). On the other hand, lack of Bonferroni procedure does not explain positive effects of ginkgo on several cognitive sub-functions as indicated by the post hoc adjustment done in this review. Adequate statistics including control of baseline differences. Similar to other aspects presumably favouring a-errors at first glance, inadequate statistical analysis also may produce b-errors. First of all, it is often far from clear what happened to outliers in baseline or outcome data and how large standard deviations seen in many studies might be explained. Regression to the mean may happen even after proper randomization especially in small samples. It seems relevant as it might explain implausible results (low better than high dose; Winther et al., 1998). This could be a function of lower baseline scores (43.8 low dose vs. 50.6 placebo vs. 46.2 high dose in the Wechsler Memory Scale). Means after 12 weeks were virtually identical (49.2 vs. 50.7 vs. 49.2). In the study of van Dongen et al. (2000), regression analysis was used to control for differences in six variables, raising the question why this was necessary given adequate randomization. Neither the regression analysis nor the stratified analyses for sub-groups are documented—therefore we just have to believe that superiority of ginkgo abolished after regression analysis. Again, this methodological problem is not restricted to early trials. For example, Hartmann and Frick (1991) found significant improvement in verbal memory after 12 weeks and Elsabagh et al. (2005a) report a mean subsequent thinking time in the Stockings of Cambridge of (5 moves-problem) of 519 ms in the placebo but of 1055 ms in the ginkgo group. Corrections for baseline differences are missing even in this recently published paper. Analysis of covariance should be done properly: for example, Mix and Crews (2002), used age Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

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as a covariate but not baseline-performance although the placebo group’s delayed recognition of faces was significantly better. Another example for inadequate stats (Birks and Grimley Evans, 2007) is the selective reporting of overall responders in the trial of Oswald et al. (1997). Their responder-definition of improvements in two out of the three tests is arbitrary and tends to neglect improvement in one of these tests (Porteus maze p ¼ 0.047; b-error). Simple ‘responder-counting’ reduces variability and quality of the data (from ordinal to nominal). The same problem arises if several trends fail to reach significance—thus suggesting use of aggregate scores (Wesnes et al., 1997). Selective reporting and interpretation in favour of ginkgo. Selective reporting of positive results enhances the risk of a-errors. For example, Stough et al. (2001) propose a treatment-related improvement after 30 days of ‘Blackmores Ginkgo Biloba Forte’ in some tests whereas ANOVAs of other variables are not mentioned. For example, the Auditory Verbal Learning Test is mentioned in the Methods section, but results are given only for sub-scores which became significant (long-term recall; Stough et al., 2001). Selective reporting is even common in papers presenting high methodological standards. For example, Wesnes et al. (1997) do not mention non-significant (simple/choice reaction time, digit vigilance test) but significant effects (Vienna determination unit). Apart from selective reporting, interpretations may also be biased: ‘Overall, of the five neuropsychologic measures included in the study that involved a timed, speed of processing component, the Ginkgo group demonstrated more improvement on four of these tasks’ (Mix and Crews, 2000; p. 226). This is simply not true as only one became significant. Taken together, whereas it is difficult to speculate about a publication bias in terms of general suppression of negative results (e.g. Birks and Grimley Evans, 2007), selective reporting became evident. b errors Problematic use of psychometric principles. Although psychometric tests have their own methodology (classical test theory), the quality of respective trials is exclusively discussed within the RCT rationale (allocation, etc.; Birks et al., 2002). Whether the psychometric instruments fulfil psychometric criteria remains unclear (objectivity, reliability, validity, norms). Inadequate application of psychometric principles seems frequent and neuropsychologists are Copyright # 2009 John Wiley & Sons, Ltd.

rarely involved (Crews et al., 2005). This might be one reason why some authors tend to remind us of textbook knowledge: ‘Outcome measures should be carefully selected to ensure that they have been documented to be reliable, valid and sensitive measures of particular neuropsychological processes, and that they decrease the possibility of familiarity/practice effects over successive administrations (e.g. alternate forms)’ (Crews et al., 2005; p. 55). Often it is not clear whether alternate forms were used. Lack of parallel forms is a severe shortcoming especially for memory tests which urged some researchers to invent their own alternate version (Winther et al., 1998). Immunization from this shortcoming may occur: ‘Parallel versions of tasks were not used because for these tests, none exist. In any case, the diverse battery used and the fact that there were only two testing points obviated the need to consider the use of alternate forms’ (Wesnes et al., 1997; p. 31). Empirical data from the same study show large improvements even in the placebo group in long-term memory which stress the need for parallel forms. Psychometric standards also comprise norms—for example Solomon et al. (2002) state that there are no norms for the Stroop interference test—which is not true. In the footnote of their results in the Wechsler Memory Scale (WMS), these authors state regarding the sub-tests digit span, logical memory and visual reproduction ‘Normative data for the WMS are for an older sample than those used in the present study (range 71–82; midpoint 76)’ (p. 838). Why are norms of this range applied if the mean age is 68.7 (ginkgogroup) and 69.9 (placebo group)? What would their results look like if percentiles instead of means would have been provided? The efficacy of ginkgo cannot be evaluated in these WMS-sub-tests as normed scores are missing (digit span, logical memory, visual reproduction). Given this situation, only the CVLT measures are left for interpretation—unfortunately they are correlated to each other. Thus, mainly digit symbol and the mental control sub-tests are left for interpretation—but the latter provide a strong ceiling effect. Thus, inadequate psychometric methodology favours berrors. Another problem is the lack of distinction between tests and scores. For example, in the same study it is not clear which of the three Stroop-sub-tests were analysed. Only colour-naming was sensitive to ginkgo in another study (Mix and Crews, 2000). Training of professionals for testing is rarely reported (Brautigam et al., 1998) although some tests yield low inter-rater-reliability if this is not reassured (Solomon et al., 2000). Contrary to neuropsychological standards, training of test procedures and practice trials Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

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are rare (e.g. Rai et al., 1991; Wesnes et al., 1987). This is a serious shortcoming as, for example, MMSEscores correlate with temporo-parietal glucose utilization only if MMSE is administered by trained professionals (Ihl, 2008). Therefore, objectivity of test administration is questionable in many trials—the same holds true for objectivity for the patients being tested. For example, van Dongen et al. (2000) did not report practice trials, but gave ambitious tests to their mostly demented subjects aged above 80 years: their low MMSE scores cast doubts that they could follow these instructions. Lack of statistical power. Sample size tends to be relatively small (Birks and Grimley Evans, 2007). Treatment intervals in healthy subjects are shorter than typically needed to produce a measurable effect in dementia (3–12 months; Ernst and Pittler, 1999). Given higher sample sizes, strong trends in the Boston naming test (Solomon et al., 2000), simple and choice reaction times (Gessner, 1985), trail making A and digit symbol (Mix and Crews, 2000) are likely to become significant. For example, Mix and Crews (2000) are left with low power of 37 subjects for their final analysis. Improvement in part A of the trail making test was three times larger after ginkgo (5.00 vs. 1.50 s). Digit-symbols showed an improvment of 12.6 s in the experimental as opposed to 5.11 s in the placebo group, but both outcome measures did not approach significance. Practice effects. Practice effects are mentioned in many trials but they are rarely controlled. For example, Elsabagh et al. (2005b) found significant retest effects in 9 of 11 dependent variables. Furthermore, such practice effects on the delayed matching to sample and PASAT were larger compared to their previous study (Hartley et al., 2003): PASAT improved p < 0.00001 at both levels of difficulty. This corresponds to more than 2 standard deviations of baseline variation seen in the placebo group. What kind of medication could outrange these practice effects? Ceiling effects. Optimal performance may not be enhanced by ginkgo and some trials do not prevent such b-errors. For example, post-prandial alertness after lunch was assessed after 1, 5, 9 and 13 weeks of ginkgo administration in young subjects aged 23.6 years although the corresponding vigilance task did not indicate any post-prandial dip at baseline (Mattes and Pawlik, 2004). There is some rationale to assess younger normals, although ceiling effects may occur: ‘Because age-related deficits in cognitive performance Copyright # 2009 John Wiley & Sons, Ltd.

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may be present in older groups without any marked symptoms or any diagnosis of cognitive impairment or dementia, we have excluded studies with any participants over the age of 60 years’ (Canter and Ernst, 2007; p. 266). On the other hand: ‘There may be a ceiling effect operating in healthy subjects and our failure to find convincing evidence for positive effects in these studies does not preclude the presence of prophylactic or therapeutic effects of the extract in people suffering from, or at risk of age-related cognitive decline and/or dementia’ (p. 276). The question ceiling effects cannot be answered unless normative values are provided and this is rarely done. Sensitivity of prose recall for coffeine in other trials (Canter and Ernst, 2007) does not rule out such b-errors in ginkgo trials. Some authors claimed that ‘identifying the enhancing effects of Ginkgo biloba extract in normal asymptomatic volunteers may be especially problematic’ because there is ‘less room for improvement than for impairment, and also because cognitive enhancers would appear to be less global in their effects than sedative drugs’ (Rigney et al., 1999; p. 414). Improvement may be more difficult to detect than sedation, because healthy subjects work at their optimum performance (Allain et al. 1993). On the other hand, ceiling effects should be taken into account when planning a study instead of complaining afterwards: ‘... because all participants appeared to be cognitively intact at the onset of this study, the majority of the neuropsychological measures may not have been of sufficient sensitivity to identify relatively subtle differences that may have actually existed...’ (Mix and Crews, 2000; p. 226). The risk for ceiling effects in normals is exaggerated if high-functioning normals are selected without giving reasons for this decision. It may reduce internal validity in terms of sensitivity change and definitely impairs external validity as generalizability of results is hampered. For example, Elsabagh et al. (2005b) enrolled post-menopausal women with a vocabulary IQ of at least 90, which is higher than the usual cut-off for normal performance (at least IQ ¼ 85). Their four groups were highly selected in terms of their crystallized intelligence, as the mean IQ was at the upper limit (IQ ¼ 114) of the normal IQ-range (85 < IQ < 115). Furthermore, some authors underestimate this source of b-errors. For example, Solomon et al. (2000) argue against the possibility of a ceiling effect. Their only argument is the possible range of raw scores. A short re-analysis of their results using the test manual proves strong ceiling effects: if their raw scores are transformed into percentiles using adequate norms, the placebo group shows almost perfect performance: Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

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at retest (week 6), the delayed logical memory raw score of the placebo group of 22 in the age range of 65– 69 corresponds to a percentile of 75 and the corresponding delayed visual reproduction raw score is 36 which corresponds to a percentile of 98 in this age group. A percentile of 75 is just below and a percentile of 98 is above the average-cut-off (85th percentile). How could any drug show superiority over placebo given this ceiling effect? The same argument applies to other tests, for example the WMS sub-test of mental control (5.6 and 5.5 points at baseline when 6.0 is optimal). Questionable sensitivity to change. In addition to practice and ceiling effects, heterogeneity might impair sensitivity: ‘The heterogeneity noted in the results of the various trials could reflect both variation in the diagnoses of patients entered and differential sensitivites of the outcome measures to the various domains of cognitive function’ (Birks et al., 2002; p. 8). Outliers and other sources of error variance impairs sensitivity to change. For example, van Dongen et al. (2000) report large standard deviations at baseline (placebo 56 vs. ginkgo 60 s in the trail making A) which outscore the numerical changes over time of both groups (þ13 placebo vs. 11 ginkgo seconds). This is in line with our speculation made above that their demented patients were not able to pass these tests. Furthermore, psychometric tests selected for specific trials are not sensitive per se: for example, digit span was not sensitive in ginkgo-trials (van Dongen et al., 2000; p. 1189). This is not surprising, as digit span forward only asks for rote rehearsal of digits presented auditorily at a rate of 1 per second. This measure is not even sensitive for monitoring decline in the early stages of Alzheimer dementia unless it is combined with a concurrent task (digit span and tracking simultaneously; Baddeley et al., 1991). Thus, negative findings concerning digit span (Table 2) are trivial (berror). Additionally, sensitivity is lowered if digit span forward (verbal short-term memory) is confounded with digit span backward (verbal working memory) and if immediate and delayed recall and recognition are reported within one single measure (e.g. van Dongen et al., 2000). In addition to these factors, sensitivity is lowered by use of short tests (Table 2). Short tests typically have low reliability as the number of items is closely linked to internal consistency and retest-reliability. High reliability is a prerequisite for sensitivity to monitor change. Furthermore, some tests will change their construct validity if they are used in samples differing from the normative populations or if they are repeated. Copyright # 2009 John Wiley & Sons, Ltd.

For example, if you have learnt which principles should be followed, you will improve at retest. It is far from clear to which of the executive and intelligence tests (Table 2) this argument applies (stockings of Cambridge, etc.; Elsabagh et al., 2005a,b). Though crucial for tapping psychometric change, reliability is mentioned in none except one of the studies included in this review (Burns et al., 2006). They calculated test-retest-correlations—unfortunately this is no way to calculate reliability as this is influenced by medication. As high internal consistencies and test-retest-reliabilities are a prerequisite for being able to monitor change, this is another serious violation of psychometric principles. Conversely, there are some hints indicating that effects of ginkgo can be detected if sensitivity is taken into account, thus encouraging the quest for sensitivity in future trials. For example, in post-menopausal women of different stages and ages, Elsabagh et al. (2005b) failed to find any significant difference between ginkgo and placebo in 11 psychometric variables. The only exception was a three-way interaction between week, treatment and stage in the intra-extra-dimensional shift task. This occurred in this sub-test which is most susceptible to ageing. Furthermore, the interaction stems from an advantage after ginkgo in the elderly group: elderly women in stage 2 ‘required fewer trials to complete the task and made fewer errors after ginkgo treatment, whereas those in stage þ1 showed no benefits’ (Elsabagh et al., 2005b; p. 173). Similarly, Singh et al. (2004) gave 7 or 10 digitis to recall with or without interference (four conditions). A time  treattreatment-interaction was confined to the ‘10 digit with interference’ condition and highly significant ( p < 0.01). Compatible with the first interpretation of our results from this review in favour of specifity, other complex measures in different tasks replicate these findings. For example, Hofferberth (1994) used different versions of the ambitious Vienna determination test. Similar to the findings of Singh et al. (2004), superiority of ginkgo raised with complexity: the moderate difficulty version yielded 12 (drug) versus 2 (placebo) more correct responses. The difference in the low difficulty version had been smaller (plus 9 vs. plus 2 correct reactions). In the most difficult version of this selective attention test, the ginkgo group improved by 22 responses which is rather different from the placebo group (plus 4 responses). CONCLUSIONS This review suggested evidence for a specific pattern of improvements achieved in RCTs using Ginkgo biloba Hum. Psychopharmacol Clin Exp 2009; 24: 345–370. DOI: 10.1002/hup

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extract. In spite of possible biases which cannot be ruled out in some trials, predominantly complex measures of memory, attention and intelligence improved. Significant changes occurred more often than expected by chance even after adjustment for number of comparisons and after correction for possible correlations between scores. Thus, the most influential factors which tend to produce a-errors could be controlled in this manner in this review. In contrary, b-errors are less discussed in other reviews though we can show that they occur frequently in the trials included and these b-errors seem to be the main source of the rather heterogenous results. Therefore, ginkgo might not have had a fair chance to demonstrate specific effects in its chronic administration to nondemented subjects, as selection of psychometric tests was rarely theoretically or empirically grounded, samples were small, treatment duration was short and reliable and modern psychometric tests sensitive to deficits and sensitive to monitor change are often lacking. Replications are missing and researchers tend to use their own measures thus lowering the comparability and the number of replications available to date. If replications are reported, these yield rather consistent results (Mix and Crews, 2000, 2002). The specific pattern identified encourages future research and respective trials should not only concentrate on JADAD scores as the only index for methodological quality but take into account psychometric standards. ACKNOWLEDGEMENTS I am grateful to Professor Petra Netter (M.D., Ph.D.) for helpful comments on earlier drafts of this paper, to Miguel Kaze´n (Ph.D.) for statistical advice and to Thomas Kubicka for friendly and professional corrections of English language.

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