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Piracetam for dementia or cognitive impairment (Review)
Flicker L, Grimley Evans J
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2012, Issue 2
http://www.thecochranelibrary.com
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
ACKNOWLEDGEMENTS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Analysis 1.1. Comparison 1 Cognition - Piracetam versus Control, Outcome 1 Immediate Memory Tests Continuous.
Analysis 1.2. Comparison 1 Cognition - Piracetam versus Control, Outcome 2 Visuospatial. . . . . . . . . .
Analysis 1.3. Comparison 1 Cognition - Piracetam versus Control, Outcome 3 MMSE. . . . . . . . . . .
Analysis 1.4. Comparison 1 Cognition - Piracetam versus Control, Outcome 4 Delayed memory continuous. . . .
Analysis 1.5. Comparison 1 Cognition - Piracetam versus Control, Outcome 5 Aphasia test. . . . . . . . . .
Analysis 2.1. Comparison 2 Global Scales Piracetam versus Control, Outcome 1 Global Scales - Continuous. . . .
Analysis 2.2. Comparison 2 Global Scales Piracetam versus Control, Outcome 2 Global Impression of Change. . .
Analysis 3.1. Comparison 3 Dependency - Piracetam versus Control, Outcome 1 Dependency Scale. . . . . . .
Analysis 4.1. Comparison 4 Depression scales - Piracetam versus Control, Outcome 1 Depression Scales - Continuous.
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
INDEX TERMS
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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i
[Intervention Review]
Piracetam for dementia or cognitive impairment
Leon Flicker1 , John Grimley Evans2
1
Western Australian Centre for Health & Ageing - WACHA, University of Western Australia, Perth, Australia. 2 Division of Clinical
Geratology, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK
Contact address: Leon Flicker, Western Australian Centre for Health & Ageing - WACHA, University of Western Australia, Royal
Perth Hospital, Box X2213, Perth, Western Australia, 6847, Australia. [email protected].
Editorial group: Cochrane Dementia and Cognitive Improvement Group.
Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 2, 2012.
Review content assessed as up-to-date: 3 January 2012.
Citation: Flicker L, Grimley Evans J. Piracetam for dementia or cognitive impairment. Cochrane Database of Systematic Reviews 2004,
Issue 1. Art. No.: CD001011. DOI: 10.1002/14651858.CD001011.
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ABSTRACT
Background
Piracetam is a drug that may enhance memory and other intellectual functions, but its usefulness in treating dementia is uncertain. It
is, however, commonly prescribed for cognitive impairment and dementia in several countries of continental Europe.
Objectives
To determine the clinical efficacy of piracetam for features of dementia (classified into the major subtypes: vascular, Alzheimer’s disease or
mixed vascular and Alzheimer’s disease, or unclassified dementia) or cognitive impairment not fulfilling diagnostic criteria for dementia.
Search methods
We searched ALOIS - the Cochrane Dementia and Cognitive Improvement Group’s Specialized Register on 4 December 2011 using
the terms: piracetam, nootropic, “2-Oxo-1-pyrrolidine”, Lucetam, Nootropil, Breinox. We identified another review by employees and
consultants of the manufacturing company, UCB Pharma (Waegemans 2002) which included data from unpublished studies not made
available to Cochrane review authors.
Selection criteria
All unconfounded, randomized, double-blind trials in which treatment with piracetam was administered for more than a day and
compared with placebo in people with dementia of Alzheimer type, vascular dementia, or mixed vascular and Alzheimer’s disease, or
unclassified dementia, or cognitive impairment not fulfilling diagnostic criteria for dementia.
Data collection and analysis
Two review authors independently extracted data from studies fulfilling the inclusion criteria. We used Intention-to-treat analysis where
feasible and pooled studies if appropriate. We planned to perform sensitivity analyses to determine if studies performing poorly on
quality criteria affected results. The pharmaceutical company marketing piracetam did not release the results of several unpublished
trials.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Main results
There were 24 included studies with 11959 participants in total. Many studies were of cross-over design and first-phase data were
unavailable, or could not be extracted. Global impression of change (GIC) was the only outcome for which pooling of data was possible,
involving only four studies. There was evidence of heterogeneity in the results, Chi2 test = 19.17 (df = 3, P < 0.001). The odds ratio
(OR) for improvement in the piracetam group compared with placebo was 3.43 (95% confidence interval (CI) 2.32 to 5.07). Using
a fixed-effect model, the OR for improvement with piracetam compared with placebo was 3.55 (95% CI 2.45 to 5.16). This estimate
was derived from completers rather than from an intention-to-treat analysis as relevant data could not be extracted from the reports.
In the limited data available, no significant differences were found between treatment and placebo groups for cognition (immediate
memory, visuospatial, Mini Mental Status Examination (MMSE), delayed memory or speech) for dependency, or for depression.
The large volume of unpublished and untraceable data not available to the review authors raises the possibility of publication bias.
Authors’ conclusions
Published evidence does not support the use of piracetam in the treatment of people with dementia or cognitive impairment. Although
effects were found on global impression of change, no benefit was shown by any of the more specific measures of cognitive function.
The evidence indicates a need for further evaluation of piracetam.
PLAIN LANGUAGE SUMMARY
Evidence for the efficacy of piracetam for dementia or cognitive impairment is inadequate for clinical use but sufficient to
justify further research
Piracetam was one of the first drugs used for dementia and comes from the class of drugs called nootropics, whose putative actions are
still poorly defined. Most of the trials of piracetam were undertaken many years ago and did not use methods which would be currently
considered standard. Some of the studies suggested there may be some benefit from piracetam but overall the evidence is not consistent
or positive enough to support its use for dementia or cognitive impairment.
BACKGROUND
Piracetam is a drug that may enhance memory and other intellectual functions through mechanisms which are ill-understood and
still debated.
has rheological and antithrombotic effects. Central and peripheral
microcirculation is supported by increased deformability of red
blood cells and by reduced adherence of damaged red blood cells
to endothelial cells.
Piracetam (2-oxo-1-pyrrolidine acetamide) was the first of the
“nootropic” drugs, so-called because of postulated effects in protecting higher brain function against external traumatic factors
such as hypoxia, electroconvulsive therapy or barbiturate poisoning. It is a cyclic derivative of gamma-aminobutyric acid (GABA)
that can cross the blood-brain barrier and is selectively concentrated in brain cortex (Vernon 1991). Even at high doses it has
no sedative, stimulant, locomotor or autonomic effects. Since its
first clinical use in 1972, three different but complementary actions have been claimed for the drug. At low dosage, piracetam
might produce cognitive enhancement by increasing oxygen and
glucose utilization through adenosine triphosphate (ATP) energy
pathways. At higher dosage, it opposes platelet aggregation and
Although not yet known in detail, it appears that one of piracetam’s
mechanisms of action may be through muscarinic cholinergic activity, although other neurotransmitters may be involved. There
are reports of an effect of piracetam on dopamine metabolism.
Piracetam appears to be well tolerated in low doses (up to 10 g
daily) and does not interact with antibiotics, anticonvulsants, analgesics, antidepressants, antihypertensives or hormone replacement
therapy (HRT). Beneficial effects of piracetam on learning and
memory have been demonstrated in several animal studies including some on older animals. There have been reports of facilitation
of memory retention over time (24 hours), failure of which is one
of the early features of Alzheimer’s disease. Similar findings have
been reported with healthy volunteers. The usefulness of pirac-
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2
etam for patients with Alzheimer’s disease, vascular dementia or
unspecified dementia is still controversial. Studies have produced
mixed results, particularly in small trials, but results from larger
trials have been more encouraging.
In spite of the uncertainties about its efficacy for dementia, either
unclassified or in one of the major subtypes (Alzheimer’s disease,
vascular or mixed), piracetam is frequently prescribed for cognitive
impairment in several continental European countries
OBJECTIVES
To determine the clinical efficacy of piracetam for the features
of dementia or cognitive impairment, either classified according
to the major subtypes of dementia: vascular, Alzheimer’s disease,
mixed vascular and Alzheimer’s disease, unclassified dementia, or
cognitive impairment not fulfilling the criteria for dementia.
The null hypotheses to be tested were that, for any of the primary
outcomes (listed below), piracetam had no effect different to that
of placebo.
These hypotheses were first be tested for all patients with dementia,
and then separately for those with Alzheimer’s disease and for
those with vascular dementia. We also considered the following
subgroup analyses.
in which treatment was administered to participants with cognitive impairment not fulfilling the criteria for dementia. We excluded trials in which the allocation to treatment or control was
not randomized, or in which treatment allocation was not concealed. Prior knowledge of treatment allocation may lead to biased
patient allocation (Schulz 1995).
In studies where a cross-over design was used, we only analyzed
data from the first treatment period, as period and order effects
cannot be reliably excluded. Studies could include a titration period prior to the randomization phase of the study. However, we
did not use data from any non-randomized titration periods to
assess safety or efficacy.
Types of participants
We included all studies in which people with dementia, either unclassified or according to the major subtypes of dementia: vascular, Alzheimer’s disease, or mixed vascular and Alzheimer’s disease,
were treated with piracetam . Unclassified dementia, Alzheimer’s
disease and vascular dementia can be diagnosed by various operational criteria, such as DSM (Diagnostic and Statistical Manual of
Mental Disorders) (APA 1987), and ICD (International Classification of Diseases), NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer’s
Disease and Related Disorders Association) (McKhann 1984). We
included Individuals with cognitive impairment not fulfilling accepted criteria for the classification of dementia.
• Age
• Sex
Types of interventions
• Severity of dementia at baseline
Piracetam at any dose with concomitant parallel placebo control
group for longer than one day of treatment.
• Dose
• Duration of treatment
Types of outcome measures
• Criteria used for diagnosis
The primary outcomes of interest were:
1. dependency;
2. global impression;
3. functional performance;
4. behavioral disturbance;
5. quality of life;
6. cognitive function (as measured by psychometric tests);
7. effect on carer;
8. death;
9. acceptability of treatment as measured by withdrawal from
trial;
10. safety as measured by the incidence of adverse effects
(including side-effects) leading to withdrawal; and
11. use of services (including institutionalization).
We did not include studies which measured only physiological
outcomes such as plasma levels, changes on functional imaging
or EEG changes but we noted these effects if the above outcomes
were part of the study.
METHODS
Criteria for considering studies for this review
Types of studies
We analyzed all unconfounded, double-blind, controlled trials,
specified as randomized, in which treatment with piracetam was
administered for more than a day and compared with placebo in
patients with dementia, either unclassified or according to the major subtypes of dementia: vascular, Alzheimer’s disease, or mixed
vascular and Alzheimer’s disease. We also analyzed those studies
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Search methods for identification of studies
Electronic searches
We searched ALOIS (www.medicine.ox.ac.uk/alois) - the
Cochrane Dementia and Cognitive Improvement Group’s (CDCIG) Specialized Register on 4 December 2011. The search terms
used were: piracetam, nootropic, “2-Oxo-1-pyrrolidine”, Lucetam, Nootropil, Breinox.
ALOIS is maintained by the Trials Search Co-ordinator and contains studies in the areas of dementia prevention, dementia treatment and cognitive enhancement in healthy. The studies are identified from the following.
1. Monthly searches of a number of major healthcare
databases: MEDLINE, EMBASE, CINAHL, PsycINFO and
LILACS.
2. Monthly searches of a number of trial registers: ISRCTN;
UMIN (Japan’s Trial Register); the WHO portal (which covers
ClinicalTrials.gov; ISRCTN; the Chinese Clinical Trials Register;
the German Clinical Trials Register; the Iranian Registry of
Clinical Trials and the Netherlands National Trials Register, plus
others).
3. Quarterly search of The Cochrane Library’s Central Register
of Controlled Trials (CENTRAL).
4. Six-monthly searches of a number of grey literature sources:
ISI Web of Knowledge Conference Proceedings; Index to
Theses; Australasian Digital Theses.
To view a list of all sources searched for ALOIS see About ALOIS
on the ALOIS website.
Details of the search strategies used for the retrieval of reports of
trials from the healthcare databases, CENTRAL and conference
proceedings can be viewed in the ‘methods used in reviews’ section within the editorial information about the Dementia and
Cognitive Improvement Group.
Additional searches were performed in many of the sources listed
above to cover the timeframe from the last searches performed for
ALOIS to ensure that the search for the review was as up-to-date
and as comprehensive as possible. The search strategies used can
be seen in Appendix 1.
Searches carried out in the previous version(s) of the review can
be viewed in Appendix 2 and Appendix 3.
The pre-publication search (December 2011) retrieved a total of
415 results. After a first-assess and a de-duplication of these results
the authors were left with 6 results to further assess.
Searching other resources
In addition, the pharmaceutical company responsible for marketing most of the piracetam worldwide, UCB SA (Pharma Sector),
had provided a comprehensive list of abstracts, which included
many unpublished studies in 1997. Unpublished, double-blind
placebo-controlled studies were reviewed when possible, although
no data have been made available.
In 2002, a systematic review Waegemans 2002 (see Excluded studies) was published. The authors of this review were employees or
consultants of UCB SA (Pharma Sector). The review included the
following unpublished or unobtainable reports: Bjurwill 1973 (Internal report); Feruglio 1973 (Internal report); Bjurwill 1974 (Internal Report); Fenyvesi 1975 (Internal report); Sourander 1975
(Internal report); Parrisius 1977 (untraceable citation); Stegink
1973 (internal report); Branconnier 1980 (Boston State Hospital report); Caro Mendivil 1983 (Internal report); Welbel 1981
(conference report). Regrettably, UCB SA (Pharma Sector) has
not responded to requests to make the data from these studies
available to the Cochrane reviewers. Reports of some other studies
believed to exist, on the basis of the list of references provided by
UCB Pharma in 1997, were not cited in the company’s review and
have so far proved impossible to retrieve (Binder 1987; Braadbaart
1974; Braadbaart 1977; Delwaide 1974; Dencker 1974; Dogan
1976; Hronek 1979; Nijdam 1974).
Data collection and analysis
Selection of studies
The original search was performed in 1997. Irrelevant citations
were discarded by a single review author (LF), based on the title
of the publication and its abstract. If we considered that an article
could possibly be relevant, we retrieved it for further assessment.
Two review authors (LF and JGE) independently reviewed the
trials for inclusion in the review from the culled citation list. We
resolved disagreements by discussion and any persisting differences
were adjudicated by a third review author (JB).
In November 2000, staff at the CDCIG editorial office repeated
the search but no new studies were identified for inclusion. Two
further duplicate publications of the Israel 1994 study were identified and 14 other new studies were identified and were added to the
exclusion list. These studies were rated by a single review author
(JGE). The search was repeated in September 2003 and revealed 11
new references, including a systematic review Waegemans 2002.
At the time of writing this update, we added 11 of these references
to the exclusion list. The search done on 11 May 2005 found no
new references. The search done on 17 December 2007 found
one new study for consideration; we excluded this study (Szalma
2006).
The search performed on 12 February 2010 identified nine new
studies, of which we included one (UCB Pharma 2007) and excluded eight. The pre-publication search performed 4 December
2011 identified 5 new studies of which all were excluded.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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Inclusion criteria
Data analysis
Category A (adequate): the report describes allocation of treatment by: (i) some form of centralized randomized scheme, such
as having to provide details of an enrolled participant to an office
by phone to receive the treatment group allocation; (ii) some form
of randomization scheme controlled by a pharmacy; (iii) numbered or coded containers, such as in a pharmaceutical trial in
which capsules from identical-looking numbered bottles are administrated sequentially to enrolled participants; (iv) an on-site
or coded computer system, given that the allocations were in a
locked, unreadable file that could be accessed only after inputting
the characteristics of an enrolled participant; or (v) if assignment
envelopes were used, the report should at least specify that they
were sequentially numbered, sealed, opaque envelopes; (vi) other
combinations of described elements of the process that provides
assurance of adequate concealment.
Category B (intermediate): the report describes allocation of treatment by: (i) use of a “list” or “table” to allocate assignments; (ii)
use of “envelopes” or “sealed envelopes”; (iii) stating the study as
“randomized” without further detail.
Category C (inadequate): the report describes allocation of treatment by: (i) alternation; (ii) reference to case record numbers, dates
of birth, day of week, or any other such approach; (iii) any allocation procedure that is entirely transparent before assignment, such
as an open list of random numbers or assignments (iv) does not
mention random allocation.
Empirical research has shown that lack of adequate allocation concealment may be associated with bias. We included trials if they
conformed to categories A or B, and we excluded those falling into
category C.
For continuous or ordinal variables (such as psychometric test
scores, clinical global impression scales, functional and quality of
life scales), we considered the main outcomes of interest were the
final assessment scores (corrected for baseline) and the changes in
score from baseline (i.e. pre-randomization or at randomization)
to the final assessment. If ordinal scale data appeared to be approximately normally distributed, or if the analysis that the investigators performed suggested parametric tests were appropriate, then
we treated the outcome measures as continuous data. The baseline assessment score is the latest available score, no longer than
two months, prior to the randomization. We grouped outcome
measures in “domains” and such domains consisted of more than
one scale. For this reason, we used standardized mean differences
(SMD) in the meta-analysis of continuous variables.
For binary outcomes such as global impression of improvement,
institutionalization and death, the endpoint itself was of interest
and we used the Peto method of the ’typical odds ratio’ (OR).
We used a standard Chi2 statistic to test for heterogeneity of the
treatment effect between the trials. If a test of heterogeneity was
negative, then we calculated a weighted estimate of the typical
treatment effect across trials, the ’typical odds ratio’ (i.e. the odds
of an unfavorable outcome amongst treatment-allocated patients
to the corresponding odds amongst controls) using Peto’s log-rank
test adapted for ordinal data (EBCTCG 1990). If, however, there
was evidence of heterogeneity of the treatment effect between trials, then we only pooled homogeneous results, or used a random-effects model (in which case the confidence intervals will be
broader than those of a fixed-effect model).
Additional hypotheses to be tested were that piracetam has no
differential effect, when compared with placebo, for certain subgroups of patients.
<
1. Age (> 65 years versus = 65 years).
2. Sex (male vs female).
3. Severity of cognitive impairment at baseline (as defined by
each cognitive scale, for example mild, Mini Mental Status
Examination (MMSE) 26-18; and moderate, MMSE 17-10).
4. Dose.
5. Duration of treatment.
Quality assessment
The same two review authors (LF and JGE) assessed the methodological quality of each trial. We rated the quality of the methodology of each selected trial for blinding and loss before analysis, as
described by Jadad 1996.
Data extraction
The same two review authors (LF and JGE) independently extracted data and we cross-checked the results. We discussed any
discrepancies.
We sought data on every patient for each outcome measure. To
allow an intention-to-treat analysis, we sought the data irrespective
of compliance, whether or not the participant was subsequently
deemed ineligible, or otherwise excluded from treatment or followup.
Studies may have included a titration period prior to the randomization phase of the study. We did not use data from these nonrandomized titration periods to assess safety or efficacy since participants were usually not randomized, nor were treatment or dose
allocations concealed.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
For this revision of the review we have restricted our criteria for
inclusion by restricting such status to those studies that were both
of acceptable quality and reported usable data. We have reviewed
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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80 studies covering a publication time span of 33 years, from
1972 until the present. There are 24 included studies with 11959
participants in total.
During that time period, piracetam has been available in many
countries in Europe, for other than investigational reasons. The
type and methods of the trials often reflect the period of time in
which the trials were performed. Many of the studies performed
were short-term, cross-over studies, a research practice popular at
one time but one that is far from ideal, especially for chronic progressive conditions such as cognitive impairment and dementia.
There was no evidence presented about the appropriate time for
wash-out for these studies nor the power of the studies to detect a
period effect. For many of these studies, possibly useful data from
the first period could not be extracted.
Over the period of time during which these studies were performed, considerable progress has been made in the classification
of dementia and cognitive impairment, and in defining subtypes
of dementia, including Alzheimer’s disease and vascular dementia.
Few of the eligible studies incorporated what would be currently
acceptable diagnostic criteria. Of the included studies, only one
defined the participants by a combination of DSM and NINCDSADRDA criteria; four of the studies used DSM criteria; three
studies used NINCDS-ADRDA criteria, and one study used ICD
criteria. It was often difficult to determine through what diagnostic filters participants had become accessible to investigators and
therefore, the generalizability of the studies is difficult to evaluate.
The range of cognitive impairments experienced by the participants ranged from minimal subjective complaints to the last stages
of severe dementia in institutionalized individuals.
The reporting of the studies was also variable in quality and reflects
reporting standards accepted at that time. Unfortunately, this often prevented the extraction of data from the studies as differences from baseline were rarely reported in continuous variables.
If means were reported, the variance was rarely indicated and the
more usual means of reporting included a rough estimate of probability that the event was due to chance. The large variation in
diagnostic criteria and the types of patients included in the study
and the paucity of data obtained, made it impossible to analyze
the subtypes of cognitive impairment or dementia separately.
There was a wide range of instruments employed to measure various aspects of cognition not only across the studies but within
individual studies. This created great problems with the multiple
comparisons within studies. The requirement that the instruments
should be sensitive to change received little emphasis. There was
little evidence that the investigators had decided on the primary
outcome measure a priori. This emphasizes the need for any interpretation of these data to be extremely conservative, as no statistical allowance has been made for multiple comparisons.
The dose of piracetam varied from 2.4 g/day to 9 g/day. The drug
appeared to be well tolerated in all studies. The relative brevity of
treatment should be emphasized; only one study (Croisile 1993),
observed treated patients for longer than six months. In view of
the chronic nature of the complaints of cognitive impairment and
dementia, and the near certainty that treatment would be required
for an extended length of time, it would have been expected that
this treatment should be studied for at least six months with data
preferably available for a full year.
Risk of bias in included studies
All included studies met at least Category B of the criterion of randomization. Some of the studies claimed to have been randomized
had disproportionate group sizes, but this was assumed to be due
to chance. Those studies that did not use the word ’randomization’
in the allocation of participants, we assumed not to be randomized
and we excluded them. In accordance with the criteria of Jadad
1996, we assessed all the included studies for blinding and withdrawals.
Only two of the included studies, (Israel 1994; Vencovsky 1980),
reported a significant number of withdrawals. The usefulness of
this measure of quality has been debated because many studies fail
to report withdrawals, and only report the participants included
in the analysis. This may well have been the case here as most
studies did not report a single withdrawal. We did not include any
of the data from these two studies in the meta-analysis because
of the inability to extract data, and therefore, there was no need
to perform a sensitivity analysis by repeating the analysis with the
exclusion of these studies.
Effects of interventions
Of the 24 included studies, only eight (total number of participants
526) yielded data. Global Impression of Change was the only outcome for which there were sufficient data for pooling, and only for
four studies (Hermann 1987; Kretschmar 1976; Macchione 1976;
Trabant 1977). The participants in Hermann 1987 were diagnosed
as having “organic brain syndrome” and those in Kretschmar 1976
and Macchione 1976 as having “psycho-organic syndromes”. The
average age of participants in the three studies (Hermann 1987;
Kretschmar 1976; Macchione 1976) ranged from 73.2 to 75 years.
All three studies reported a significant benefit from piracetam.
Trabant 1977, the smallest of the four studies, enrolled participants with “cerebrovascular insufficiency” with an average age of
only 59 years. This study resulted in a non-significant difference
favoring the control group. There was evidence of heterogeneity
in the results from the four studies, Chi2 test = 19.17 (df = 3, P <
0.001). Overall, the Peto OR for improvement in the piracetam
group compared with the placebo group was 3.43 (95% CI 2.32 to
5.07, P < 0.00001) (Analysis 2.2). This estimate was calculated on
the basis of completers’ data rather than intention-to-treat which
could not be extracted from the reports.
The evidence of effects on cognition and other measures, was inconclusive. In the limited data available, no significant differences
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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were found between treatment and placebo groups for cognition
(immediate memory, visuospatial, MMSE, delayed memory or
speech) for dependency, or for depression.
Implications for research
DISCUSSION
The potential use of this drug could be further evaluated by the
following methods.
Despite widespread use of piracetam, the evidence for its efficacy
is poor in quality and quantity. Many of the studies have been
performed on participants who were not classified with the use of
standardized criteria. The participants have been treated for short
periods of time - the vast majority were studied for three months
or less. The use of objective, standardized cognitive scales that are
sensitive to change was another serious omission in this body of
evidence. Many studies evaluated multiple outcome measures, and
made no adjustment for multiple comparisons. Often, the reports
did not include the data from which the comment “no significant
differences between groups” was made.
Of the outcomes assessed in this review, only impression of global
change provided sufficient data for inclusion in a meta-analysis,
and for this only four trials could be included. This finding is comparable with that of Waegemans 2002, as was the overall beneficial
effect apparently associated with piracetam. There was significant
heterogeneity between studies and the relevance of the diagnostic
categories used by the investigators to modern concepts of dementia and cognitive impairment is uncertain. The findings must be
viewed as tentative since, in addition to the paucity of data available for meta-analysis, the considerable amounts of unpublished
and untraceable data not available to the review authors raises the
possibility of publication bias.
The limited evidence of benefit in short-term studies on subjective
global impression involving participants with clinical features suggestive of dementia or cognitive impairment is sufficient to justify
further research and a full publication of all the past studies.
1. An individual patient data (IPD) review would yield
valuable information about the size of effects over time as well as
within particular diagnostic groups. The large volume of
currently unpublished and inaccessible data should be made
available for such a review.
2. Pending a full analysis of all unpublished data there may be
a need for further randomized trials of piracetam in patients with
the diagnosis of dementia of Alzheimer type or vascular dementia
made by currently accepted diagnostic criteria - ICD 10, or DSM
IV, or NINCDS-ADRDA. Trials of piracetam should last at least
six months and preferably longer. Global cognitive instruments
which are sensitive to change, e.g. ADAS (Alzheimer’s Disease
Assessment Scale), should be used as primary outcome measures
as well as the Clinician Global Impression of Change (CGIC).
Effects of piracetam on levels of dependency and caregiver
quality of life should also be incorporated in such studies.
ACKNOWLEDGEMENTS
Implications for practice
Dr Flicker carried out the first version of this review whilst on
sabbatical leave from the University of Melbourne in 1997. Dr
Flicker gratefully acknowledges the encouragement and advice of
Mr Peter Smith, CDCIG Co-ordinator and Ms Jacqueline Birks,
CDCIG Statistician during that period.
At this stage, the evidence available from the published literature
does not support the use of piracetam in the treatment of people
with dementia or cognitive impairment.
Ms Dymphna Hermans performed the update searches in November 2000, September 2003 and May 2005. Vittoria Lutje carried
out the update search of December 2007.
AUTHORS’ CONCLUSIONS
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
7
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(3-4):393–407. [MEDLINE: 56-06574]
Saletu 1980a {published data only}
Saletu B, Grunberger J, Linzmayer L. Quantitative EEG
and psychometric analyses in assessing CNS-activity of Ro
13-5057-a cerebral insufficiency improver. Methods and
Findings in Experimental and Clinical Pharmacology 1980;2
(5):269–85.
Saletu 1980b {published data only}
Saletu B, Grunberger J, Linzmayer L. Quantitative EEG
and psychometric analyses in assessing CNS-activity of Ro
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(5):269–85. [MEDLINE: 1987256328]
Saletu 1984 {published data only}
Saletu B, Grunberger J, Linzmayer L, Stohr H.
Encephalotropic and psychotropic effects of intravenous
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Samorajski 1985 {published data only}
Samorajski T, Vroulis GA, Smith RC. Piracetam plus
lecithin trials in senile dementia of the Alzheimer type.
Annals of the New York Academy of Sciences 1985;444:
478–81. [MEDLINE: 73-18096]
Scheef 1983 {published data only}
Scheef WTI. Psychotic states of mind in the course
of ifosfamide therapy and prevention with piracetam
(Nootrop). Preliminary report [Psychotische Zustandsbilder
im Verlauf der Ifosfamid–Therapie und Verh³tung
durch Piracetam (Nootrop)]. Munchener Medizinische
Wochenschrift 1983;125:35–6.
Sebban 1994 {published data only}
Sebban C, Poitrenaud J. Correlation between psychmetric
and EEG parameters in a controlled trial of piracetam in
demented patients. Conference proceedings Symposium
Piracetam: 5 years progress in Pharmacology and Clinics;
29 April, 1994; Athens. 1994:167–9.
Skondia 1985 {published data only}
Skondia V, Kabes J. Piracetam in alcoholic psychoses:
a double-blind, crossover, placebo controlled study.
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[MEDLINE: 1985231496]
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disease. Psychopharmacology Bulletin 1984;20(3):542–5.
[MEDLINE: 1984298859]
Snel 1983 {published data only}
Snel H, Lehmann E, Velikonja M. Piracetam in the
treatment of alcohol-induced delirium [Piracetam in
der Behandlung des alkohlobedingten Delirs]. MMWMunchener Medizinische Wochenschrift 1983;125(42):
947–9.
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Stegink AJ. The clinical use of piracetam, a new nootropic
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[MEDLINE: 1972254218]
Szalma 2006 {published data only}
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comparative clinical, experimental and psychological
studies. MBI Medico-Biologic Information 1980;6:26–34.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
12
Temkov 1980b {published data only}
Temkov I, Yordanov Y, Konstantinov K. Clinical and
experimental-psychological studies of the Bulgarian drug
pyramem. Savremenna Medicina 1980;31(9):467–74.
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American Psychiatric Association, 1987.
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Schulz 1995
Schulz KF, Chalmers I, Hayes RJ, Altman DG. Failure to
conceal treatment allocation schedules in controlled trials
influences estimates of treatment effects: an analysis of
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Waegemans 2002
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Cognitive Disorders 2002; Vol. 13, issue 4:217–24.
References to other published versions of this review
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
13
Flicker 2004
Flicker L, Grimley Evans J. Piracetam for dementia
or cognitive impairment. Cochrane Database of
Systematic Reviews 2004, Issue 1. [DOI: 10.1002/
14651858.CD001011]
∗
Indicates the major publication for the study
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
14
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Chouinard 1983
Methods
Randomized, double-blind, placebo-controlled, parallel-group study
Participants
60 participants with mild diffuse cerebral impairment, 22 men and 38 women. Diagnoses
included schizophrenia (n = 34) affective disorder (n = 24) or mild organic brain syndrome
(n = 2). Age range 54 to 80 years
Interventions
3 groups treated for 12 weeks 1) piracetam 2.4 g/day; 2) piracetam 4.8 g/day; 3) placebo
Outcomes
SCAG scale, Crichton Geriatric Rating Scale, Nurse-adminstered 6-point CGI, BPRS,
WAIS, Wechsler Memory Scale, Rey figure, Extrapyramidal Rating Scale of Chouinard
Notes
No usable data extractable. Adjusted scores presented without indication of variance. Not
mentioned by Waegemans 2002.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Croisile 1993
Methods
Randomized, double-blind, placebo-controlled parallel-group study
Participants
33 participants with a diagnosis of probable Alzheimer’s Disease made by NINCDS
ADRDA criteria. Only 30 completed the study, 18 female - mean age 66.1 (7.8) years
Interventions
Piracetam 8 g/day or placebo given for 1 year.
Outcomes
MMSE
MADRS
ADL (Blessed A)
Language by the Aphasia Battery
Visuo-verbal Learning Test
Rey 1,2 and 3
Three digit span tests
Remote semantic memory
Recent incident memory
Logical memory
Notes
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
15
Croisile 1993
(Continued)
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Davidson 1987
Methods
Randomized, double-blind, placebo-controlled factorial cross-over trial including lecithin
Participants
7 men 3 women met NINCDS-ADRDA criteria for Alzheimer’s Disease. T-design with
data from first phase not extractable. Concealment not clear
Interventions
Treatment for 1 week only. Three groups: 1) piracetam 8g/day plus lecithin; 2) piracetam
8g/day plus placebo; 3) double placebo
Outcomes
ADAS total scores.
Notes
Data from first period not extractable.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Unclear risk
B - Unclear
Diesfeldt 1978
Methods
Randomized double-blind placebo-controlled cross-over study.
Participants
8 participants, all women, who were inpatients in a psychogeriatric nursing home. Mean
age 80.6 years, range 73 to 89 years
Interventions
3 phases of 15 weeks. First phase run-in for all participants. Second and third phases
participants randomly allocated to piracetam 4.8 g/day or placebo
Outcomes
Used the Beoordelingsschaal voor Oudere Patienten (BOP) score which is a 35-item scale
in which factor analysis has demonstrated 6 groups - Dependency 1, Aggressiveness 2, 3a)
, physical disability 3b) depression, 3c) mental disability, and 4) Inactivity.
Also Lowenfeld Mosaic Test and Isaacs Block Sorting.
Notes
Risk of bias
Bias
Authors’ judgement
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Support for judgement
16
Diesfeldt 1978
(Continued)
Allocation concealment (selection bias)
Low risk
A - Adequate
Fioravanti 1991
Methods
Double-blind placebo-controlled cross-over design.
Participants
90 “geriatric” participants with mild to moderate cognitive impairment. 84, 50 men and
34 women, completed the study. Mean age 72.1 years
Interventions
2 phases each of 8 weeks separated by a 4-week wash-out. Participants given either piracetam
6g/day for 4 weeks followed by piracetam 3 g/day for 4 weeks or placebo for 8 weeks
Outcomes
SCAG scale, HRSD, TP Test, RMT, Labyrinth Test, Behavioural Observation Test
Notes
Data from the first period of the cross-over design not extractable
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Fleischhacker 1986
Methods
Randomized, double-blind, placebo-controlled, parallel-group study
Participants
24 participants with evidence of organic mental disorder due to alcohol. The study did
not commence until manifestations of acute alcohol withdrawal had subsided. 17 men, 7
women, aged 20 to 55 years
Interventions
3 groups treated for 42 days: piracetam 24 g/day, piracetam 6 g/day, placebo
Outcomes
SKT subtests A to E, Verbal Comprehension Test, d-2 test, Pauli Test (attention and
concentration, Critical Flicker Fusion
Notes
Data not extractable from published report.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
17
Gainotti 1989
Methods
Randomized, double-blind, placebo-controlled parallel study.
Participants
45 patients with history of slowly progressive deterioration of cognitive function and labeled
as dementia but not classified by any criteria. (Excluded multi-infarct dementia cases by
Hachinski score)
Interventions
3 groups each treated for 90 days: 1) piracetam 2.4 g/day; 2) oxiracetam 2.4 g/day; 3)
placebo
Outcomes
Rey’s 15-word memory test, Immediate visual memory, word fluency and phrase construction, Raven’s colored matrices (visuospatial), copying drawings
Notes
Data from tests could not be extracted.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Unclear risk
D - Not used
Growdon 1985
Methods
4 studies described - only “experiment 1” fulfilled criteria of unconfounded placebo-controlled study. This study was a randomized double-blind cross-over study
Participants
4 participants who probably fulfilled NINCDS-ADRDA criteria for Alzheimer’s disease.
Aged 56 to 70 years, 2 male participants
Interventions
Piracetam 6.6 g/day for 3 weeks.
Outcomes
Neuropsychological battery.
Notes
Scores not presented. Reported that 3/4 better on piracetam than placebo but order of
treatment of cross-over not given
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Unclear risk
B - Unclear
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
18
Gustafson 1978
Methods
Randomized, double-blind, cross-over study with 3 treatments - 4 weeks on each treatment
with 4 weeks wash-out between treatments
Participants
9 participants, mean age 61.7 (10.2) years range 48 to75. Cognitive complaints with no
definite criteria
Interventions
Piracetam 4.8 g/day; piracetam 9.6 g/day; placebo.
Outcomes
Critical flicker fusion Reaction Time (RT), Colour Word Test, Verbal Memory Digit Span,
Sequence memory
Notes
Reports no significant changes, but no data presented. No extractable data
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Hermann 1987
Methods
Randomized, double-blind, placebo-controlled, parallel-group study
Participants
130 psychogeriatric inpatients with organic brain syndrome as determined by ICD. The
participants were aged between 65 and 85 years, mean age 75 years, 80 female and 50 male
Interventions
Piracetam 4.8g/day or placebo for 12 weeks.
Outcomes
SCAG scale
BGP
CGI
SKT
BT
Notes
Data for SCAG, BGP, SKT and BT were not able to be extracted
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
19
Israel 1994
Methods
Double-blind, randomized trial.
3 randomized parallel groups which were then given a memory training program in a crossover study design
Participants
162 participants, 26 men and 136 women mean age of 68.7 (7.8) years. They fulfilled
working criteria for age-associated memory impairment i.e. they complained of memory
complaints and scored 1 SD below the mean for young adults on Israel’s (1988) test battery.
They all scored greater than 26 on MMSE
Interventions
3 groups - Piracetam 4.8 g/day, Piracetam 2.4g/day and Placebo for 3 months.
However because much of the study design is confounded with memory training program
only half the participants had 6 weeks of treatment unconfounded with memory training
program
Outcomes
Free recall memory tests - Israel’s Memory Battery (Israel 1988), Reys Word Repitition Test
and Memory Functioning Questionnaire, a Cognitive Difficulties Scale, participants’ own
rating of memory abilities on a 7-point Likert scale.
Global evaluation on a 4-point scale
Notes
27 patients withdrew, 10 patients during the first half. Used a cross-over analysis and no
data presented for parallel group analysis and unable to extract data unconfounded for
memory training
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Unclear risk
B - Unclear
Kretschmar 1976
Methods
2 studies presented only 1 in detail.
Double-blind, placebo-controlled, randomized, parallel study
Participants
There were 78 participants, 61 women 17 men, with average age of 73.2 years. All participants were diagnosed with the psycho-organic syndrome of old age
Interventions
Piracetam 4.8 g/day for 6 weeks or placebo.
Outcomes
Based on a 20-item symptom rating scale of Gottfried, Cronholm and Schalling, with
global interpretation of improvement or not
Notes
Data presented on the scale of Gottried et al. unable to be extracted. 27/39 patients on
high dose piracetam improved on CGI compared with 12/39 patients on placebo. Note
two duplicate publications
Risk of bias
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
20
Kretschmar 1976
(Continued)
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Lloyd-Evans 1979
Methods
Randomized, double-blind placebo-controlled cross-over study
Participants
102 (not 109) participants from old people’s residential homes said to have “dementia” or
“chronic brain failure” but no diagnostic criteria used
Interventions
12 weeks of piracetam 2.4 g/day or placebo.
Outcomes
Arteriosclerosis Score derived from a medical examination, ADL score, MSQ, and a battery
of 19 items from 7 psychological tests which include memory, language, planning and
registration. However, the data from the medical examination and ADL were not presented
Notes
Did not use ITT analysis. Only data from 78 of 102 participants available because of
administration and compliance difficulties in 24 participants. In addition, no markers of
compliance in 43 participants, and 6 participants developed intercurrent illness resulting in
a second analysis of 29 patients. Analysis was only presented utilizing the cross-over design.
Data could not be extracted from the report of the study
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Macchione 1976
Methods
Randomized, double-blind, placebo-controlled, parallel study
Participants
182 participants (172 in some parts of the manuscript) mean age 74.6 (10.4) years longterm residents in a geriatric home. All suffered with cerebral psycho-organic syndrome. No
standardized criteria given
Interventions
Piracetam 2.6 g/day (1.6 g orally and 1 g intramuscular injection) or placebo for a period
of 6 to 8 weeks
Outcomes
Overall assessment, symptoms of asthenia, anxiety, psychomotor disturbances, memory
disturbances, inability to adapt to surroundings and distraction assessed on a three point
scale - improvement, no change and worse
Notes
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
21
Macchione 1976
(Continued)
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Unclear risk
B - Unclear
Mindus 1976
Methods
Randomized, double-blind, placebo-controlled, cross-over study
Participants
18 normal participants median age 56 years, range 47 to 73.
Interventions
2 periods, piracetam 4.8 g/day for 4 weeks as opposed to placebo for 4 weeks
Outcomes
Digit Symbol Test Bourdon-Wiersma Test, Spoke Test, patient self-rating, global impression
of psychologist Two choice reaction time, critical flicker fusion, Krakau Visual Acuity
Tapping
Notes
Data could not be extracted for first period of study.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Parnetti 1985
Methods
Randomized, placebo-controlled, 2 x 2 factorial, parallel-group study
Participants
80 participants with less then 6 months “mental deterioration”. No standardized criteria
used. All participants aged over 65 years, mean 72 (9) years
Interventions
4 Groups
1) Placebo
2) Piracetam 4.8 g/day
3) Pentoxifylline 1.2 g/day
4) Pentoxifylline 1.2 g/day plus piracetam 4.8 g/day
All treatments given for 12 weeks, wash-out for 4 weeks and then same treatment again for
11 weeks
Outcomes
Verbal Fluency test (WF)
Sentence Construction (SC)
Rey’s 15 words (15W)
Visuo-spatial tests (PM’47),
Immediate Visual Memory (IVM), and
Constructive apraxia (CA)
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
22
Parnetti 1985
(Continued)
Notes
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Pierlovisi 1991a
Methods
Two studies; both included.
Both studies randomized, double-blind, placebo controlled, parallel studies.
First study presented here.
Participants
Study 1 - 12 patients, 6 males and 6 females, mean age 64 years, range 61 to 75 years with
a diagnosis of probable Alzheimer’s Disease made on DSM III R and NINCDS ADRDA
criteria
Interventions
Study 1 - Two groups, piracetam 9 g/day or placebo.
Outcomes
EEG studies
Trail making Test A
Tests of dementia (BEDc) Signoret et al 1988
WAIS
Notes
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Pomara 1984
Methods
Randomized, double-blind, placebo-controlled, cross-over study
Participants
9 participants, 5 males and 4 females, mean age 67 (range 55 to 75), all met DSM III
criteria for Primary Degenerative Dementia
Interventions
3 periods, each of 2 weeks. No wash-out period.1) placebo + placebo; 2) piracetam 4.8 g/
day plus placebo; 3) piracetam 4.8 g/day plus lecithin 20 g/day
Outcomes
Buschke’s Selective Reminding TaskSimple visual reaction Time Sperling Task
Notes
Unable to extract data from first period.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
23
Pomara 1984
(Continued)
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Reisberg 1982
Methods
Two studies reported in this paper. The first study is a randomized, double-blind, placebocontrolled, cross-over study and is included.The second study is an uncontrolled open study
of piracetam combined with choline and is not included
Participants
20 participants, 12 females and 8 males, mean age 71.5 years range 61 to 85 years all with
a diagnosis of primary degenerative dementia made by DSM- III criteria
Interventions
2 periods of 4 weeks separated by a 1 week wash-out period. One period of piracetam 7.2
g/day, the other of placebo
Outcomes
Verbal memory
Visual memory
Verbal associative memory
Associative memory
Perceptual speed
Flexibility of closure
Digit symbol substitution test
Continuous performance test
Notes
Impossible to extract data from first phase from published report
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Sano 1990
Methods
Double-blind, randomized, placebo-controlled, parallel-group study
Participants
20 patients with Parkinson’s disease. 19 of these patients also met DSM III criteria for dementia and the other patient had moderate cognitive impairment. Mean age approximately
73 years range 49 to 84
Interventions
Two groups:
1) Piracetam 3.2 g/day for 12 weeks followed by 4.8 g/day for 12 weeks
2) Placebo
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
24
Sano 1990
(Continued)
Outcomes
Modified MMSE maximum Score 57
Buschke’s SRT
Digit symbol subtest of the WAIS (DSYM) - A test of visual motor performance
Controlled Word Association Test (CFL)
Category Naming (CATEG)
Reaction Time (RT)
Continuous Performance Task
SIP, completed by informant
Global rating of neuropsychological performance
Notes
5 participants did not complete the study, 4 in the piracetam group and 1 in the placebo.
Data presented in paper have been reclassified into a 3-point ordinal scale and are not able
to be extracted. Neuropsychological global rating has been assumed to represent clinical
global assessment
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Schmidt 1991
Methods
Randomized, double-blind, placebo-controlled, parallel-group study
Participants
101 motorists who scored in the lower half in the Vienna determination test (reaction
capacity). Mean age 62 years, range 48 to 76 years
Interventions
Two groups treated for 42 days piracetam 4.8 g/day versus placebo
Outcomes
Emotionality inventory (EMI-B)Tracking/Reaction test for driving performance.
Driving performance tests.
Notes
5 participants (3 from the piracetam group and 2 from the placebo group) were excluded
from the analysis. The use of only specific driving orientated tests resulted in no data being
extractable
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
25
Trabant 1977
Methods
Randomized, double blind, placebo-controlled, parallel-group study
Participants
40 participants labeled with “cerebrovascular insufficiency”. Average age 59 years with 42%
female
Interventions
Piracetam 4.8 g/day or placebo for 6 weeks.
Outcomes
Used a scale based on 13 symptoms rated as better, unchanged or worse.
Also used a subjective rating scale determined by the researcher of improvement compared
with previous treatment - this is in essence a clinical global impression
Notes
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
UCB Pharma 2007
Methods
Randomized, double-blind, placebo-controlled, parallel-group study
Participants
676 participants with mild cognitive impairment aged between 50 to 89 years
Interventions
Three groups piracetam 4.8 g/day, piracetam 9.6 g/day for 52 weeks or placebo
Outcomes
CBCS based on multiple tests inadequately described.
Notes
Other outcomes included Clinician Interview-Based Impression of change-Plus, ADL inventory, MMSE, BSI, and Global Deterioration scale. These outcomes were not described
in the report
For the primary outcome of CBSC, the report claimed “For piracetam 4.8 g/day versus
placebo there was a difference of -0.291 [95% CI: -0.787, 0.206] at month 12 on the CBCS
and a P value of 0.251 for the Intent-To-Treat (ITT) population. For piracetam 9.6g/day
versus placebo there was a difference of -0.298 [95% CI: -0.790, 0.193] at month 12 on
the CBCS and a p-value of 0.234 for the ITT population.” There were too few details in
this report to verify this
Risk of bias
Bias
Authors’ judgement
Allocation concealment (selection bias)
Low risk
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Support for judgement
26
Vencovsky 1980
Methods
Randomized, double-blind, placebo-controlled, parallel-group study
Participants
43 patients from a psychogeriatric hospital - all participants greater than 65 years of age,
14 men and 29 women said to have senile or atherosclerotic dementia but no diagnostic
criteria used.
Piracetam group’s average age was 71 years and in the placebo group 76 years
Interventions
Two groups - piracetam 2.4 g/day for 6 weeks or placebo.
Outcomes
EEG
Q scale of Gottfries and Cronholme (psychological inventory)
Weschler’s Memory Test
OHP Scale - Observational scale by Intermediate medical staff
Notes
Paper was translated from the original Czech.
92 participants started the treatment. 14 did not finish the study, another 14 died and the
remaining 21 patients were ongoing at the time of the study report.
Data could not be extracted from the published report.
Risk of bias
Bias
Authors’ judgement
Support for judgement
Allocation concealment (selection bias)
Low risk
A - Adequate
ADAS: Alzheimer’s Disease Assessment Scale
ADL: Activities of Daily Living score
BGP: Beurteilungsskala fur geriatrische Patienten
BPRS: Brief Psychiatric Rating Scale
BSI: Brief Symptoms Inventory
BT: Benton Test
CBCS: Cognitive Battery Composite Score
CGI: Clinical Global Improvement
DSM-III: Diagnostic and Statistical Manual of Mental Disorders, 3rd edition
HRSD: Hamilton Rating Scale for Depression
ICD: International Classification of Diseases
ITT: intention-to-treat
MADRS: Mongomery and Ashberg Depression Rating Scale
MMSE: Mini Mental Status Examination
MSQ: Mental Status Questionnaire
NINCDS-ADRDA: National Institute of Neurological and Communicative Disorders and Stroke - Alzheimer’s Disease and Related
Disorders Association
RMT: Randt Memory Test
RT: Reaction Ttime
SCAG: Sandoz Clinical Assessment Scale
SD: standard deviation
SIP: Sickness Impact Profile
SKT: Syndromkurztest subtests
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
27
SRT: Selective Reminding Test
TP: Toulouse-Pierron attention test
WAIS: Weschler Adult Intelligence Scales
Characteristics of excluded studies [ordered by study ID]
Study
Reason for exclusion
Abuzzahab 1977
Report does not mention randomization.
Abuzzahab 1978
Report does not mention randomization.
Aguglia 1995
No placebo group.
Barantsevich 2009
This study was not randomized.
Barnas 1987
This study assessed piracetam in the treatment of symptoms of alcohol withdrawal and not for cognitive
impairment or dementia
Barnas 1990
This study assessed Piracetam in the treatment of the symptoms of alcohol withdrawal and not for cognitive
impairment or dementia
Bertoldin 1990
Report does not mention randomization.
Binder 1974
Used in the treatment of chronic alcoholism not for cognitive impairment or dementia
Binder 1976
Piracetam used in the treatment of chronic alcoholism not for dementia or cognitive impairment
Borkowska 2011
Not an RCT
Borromei 1985
No placebo group.
Bugrova 2007
No randomized control group.
Buranji 1990
Assessment of piracetam for acute alcohol withdrawal, not dementia or cognitive impiarment
Chen 2011
No placebo control group
Chouinard 1981
Duplicate publication of Chouinard 1983.
Corona 1983
Outcome measure not cognitive function.
Corona 1989
Confounded.
Deberdt 1994
A review only.
Degirmenci 2006
Not randomized.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
28
(Continued)
Delwaide 1975
Study is double-blind but does not mention randomization.
Destee 1984
Outcome measure not cognitive function.
Dormehl 1999
No measure of function.
Eckmann 1976
Randomized, double-blind, parallel-group study of two doses of piracetam against placebo, but diagnosis
not dementia (depression or paranoid depression of the second half of life)
Friedman 1981
No placebo control and confounded with choline.
Gallai 1991
“Single-blind” study.
Gertz 1983
Review only.
Gouliaev 1994
Review only.
Growdon 1986
Duplicate publication of Growdon 1985.
Gualtieri 2002
Review - no new data on piracetam.
Herrmann 1991
Summarizes data obtained from paper by Hermann 1987.
Herrmann 1992
Re-analysis of study of Hermann 1987.
Holinski 2008
Patients do not have dementia or cognitive impairment. Test of prophylaxis to future cognitive impairment
following surgery
Holinski 2011
Participants did not have a diagnosis of cognitive impairment
Hollander 1986
Review - no data on study of piracetam.
Ince 2008
Patients did not have dementia or cognitive impairment ? they had cerebellar ataxia
Iznak 2010
No non-treatment control group
Kartin 1979
Assesses the use of piracetam in acute stroke rather than in dementia and cognitive impairment
Kountouris 2000
Not a study evaluating piracetam as piracetam given to all participants. A study of intravenous immunoglobulin
Larson 1993
N = 1 study, i.e. there was only one patient treated with piracetam in a multiple cross-over design
Libov 2007
Patients did not have dementia or cognitive impairment. Patients were included with tardive dyskinesia
associated with chronic schizophrenia
Lu 2000
Piracetam treatment was confounded with choline.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
29
(Continued)
Mateo 1996
Outcome measure is hemichorea, not cognitive function.
Mielke 1996
Not a study - commentary only.
Mondadori 1996
Review only.
Moriau 1993
Outcomes only included cellular physiological measures and not clinical outcomes
NCT01009476
Not an RCT.
Neznamov 2008
No placebo group ? piracetam compared with a new nootropic called noopept. No diagnosis of dementia or
cognitive impairment, 37 patients with CNS diseases of vascular origin (aged over 50 years) and 16 patients
with post-traumatic CNS damage
Oepen 1985
Did not use randomized control group but used age matched controls instead
Olivella 1981
No placebo group.
Parnetti 1991
No placebo group.
Passeri 1990a
Two similar parallel groups but not random allocation.
Passeri 1990b
No analyzable data.
Platt 1993
Piracetem used for the treatment of acute stroke.
Prud’homme 1990
Cross-over design; data from first phase not extractable.
Prud’homme 1994
Described as trial but no analyzable data.
Rainer 2001
Not a trial - no control group.
Romildo-Bueno 1974
Study of the use of piracetam in detoxification of people with alcohol abuse
Saletu 1980a
No placebo group; outcome measure not cognitive function.
Saletu 1980b
Piracetam not given for more than one dose ie not more than one day
Saletu 1984
Piracetam not given for longer than 1 day.
Samorajski 1985
Confounded with lecithin.
Scheef 1983
Confounded with Ifosfamid.
Sebban 1994
No analyzable data.
Skondia 1985
Used for alcohol withdrawal not dementia or cognitive impairment
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
30
(Continued)
Smith 1984
Confounded with lecithin.
Snel 1983
Assessment of treatment for alcohol withdrawal not cognitive impairment or dementia. Study also confounded with chlormethiazol
Stegink 1972
Report does not mention randomization.
Szalma 2006
This study did not examine participants with cognitive impairment or dementia. The participants were
cognitively “healthy”. They had a MMSE > 20 and were not allowed to have a prior diagnosis of a psychiatric
disorder or a primary degenerative CNS disorder
Tariska 2000
No control group - An open-label, phase 4 study of people with dementia and mild cognitive impairment
Temkov 1980a
Study does not mention random allocation to study groups.
Temkov 1980b
Duplicate publication (in Bulgarian) of Temkov 1980a
Tsolaki 1995a
Contact with investigators - study was open with no randomization - all participants were given a treatment
period of vitamins followed by piracetam
Tsounis 1994
Does not measure cognitive function.
Tudorache 1990
Confounded with lecithin.
Vernon 1991
Review only.
Vlietinck 1993
Re-analysis of three previous studies for cost effectiveness
Wang 1999
No control group - comparison between piracetam and huperzine A
Wasilewski 1981
No evidence of randomization with groups of vastly different size. Also no placebo group - a comparison of
4 active treatments.
Translated form Polish.
Wolters 1992
Piracetam and placebo used as controls for a trial of vinpocetine. No usable data
Yonchev 1991
Participants not randomized - observational study.
Zavadenko 2009
Presence of control group no mention of randomization. Patients had closed craniocerebral trauma and not
dementia or cognitive impairment
Zirm 1994
No placebo control group - nimodipine was compared with piracetam
CNS: central nervous system
MMSE: Mini Mental Status Examination
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
31
DATA AND ANALYSES
Comparison 1. Cognition - Piracetam versus Control
Outcome or subgroup title
1 Immediate Memory Tests
Continuous
2 Visuospatial
3 MMSE
4 Delayed memory continuous
5 Aphasia test
No. of
studies
No. of
participants
3
78
Std. Mean Difference (IV, Fixed, 95% CI)
0.25 [-0.20, 0.70]
2
1
2
1
66
30
66
30
Std. Mean Difference (IV, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)
Std. Mean Difference (IV, Fixed, 95% CI)
Mean Difference (IV, Fixed, 95% CI)
0.18 [-0.31, 0.66]
1.8 [-3.29, 6.89]
0.19 [-0.30, 0.67]
2.66 [-2.07, 7.39]
Statistical method
Effect size
Comparison 2. Global Scales Piracetam versus Control
Outcome or subgroup title
1 Global Scales - Continuous
1.1 Global Scale
2 Global Impression of Change
No. of
studies
No. of
participants
2
2
4
20
430
Statistical method
Std. Mean Difference (IV, Fixed, 95% CI)
Std. Mean Difference (IV, Fixed, 95% CI)
Peto Odds Ratio (Peto, Fixed, 95% CI)
Effect size
Subtotals only
0.27 [-0.62, 1.17]
3.43 [2.32, 5.07]
Comparison 3. Dependency - Piracetam versus Control
Outcome or subgroup title
1 Dependency Scale
No. of
studies
No. of
participants
2
38
Statistical method
Std. Mean Difference (IV, Fixed, 95% CI)
Effect size
-0.28 [-0.93, 0.37]
Comparison 4. Depression scales - Piracetam versus Control
Outcome or subgroup title
1 Depression Scales - Continuous
No. of
studies
No. of
participants
1
30
Statistical method
Mean Difference (IV, Fixed, 95% CI)
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Effect size
1.46 [-4.79, 7.71]
32
Analysis 1.1. Comparison 1 Cognition - Piracetam versus Control, Outcome 1 Immediate Memory Tests
Continuous.
Review:
Piracetam for dementia or cognitive impairment
Comparison: 1 Cognition - Piracetam versus Control
Outcome: 1 Immediate Memory Tests Continuous
Study or subgroup
Piracetam
Std.
Mean
Difference
Placebo
Weight
N
Mean(SD)
N
Mean(SD)
Croisile 1993
14
-0.36 (2.5)
16
-1.44 (2)
37.7 %
0.47 [ -0.26, 1.20 ]
Parnetti 1985
18
3.3 (11)
18
1.8 (11.5)
46.7 %
0.13 [ -0.52, 0.78 ]
6
-1.64 (17.5)
6
-4 (30.1)
15.6 %
0.09 [ -1.04, 1.22 ]
100.0 %
0.25 [ -0.20, 0.70 ]
Pierlovisi 1991a
Total (95% CI)
38
IV,Fixed,95% CI
Std.
Mean
Difference
IV,Fixed,95% CI
40
Heterogeneity: Chi2 = 0.55, df = 2 (P = 0.76); I2 =0.0%
Test for overall effect: Z = 1.10 (P = 0.27)
Test for subgroup differences: Not applicable
-4
-2
0
Favours placebo
2
4
Favours piracetam
Analysis 1.2. Comparison 1 Cognition - Piracetam versus Control, Outcome 2 Visuospatial.
Review:
Piracetam for dementia or cognitive impairment
Comparison: 1 Cognition - Piracetam versus Control
Outcome: 2 Visuospatial
Study or subgroup
Piracetam
Std.
Mean
Difference
Placebo
Weight
IV,Fixed,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Fixed,95% CI
Croisile 1993
14
-0.67 (7.58)
16
-1.59 (4.56)
45.4 %
0.15 [ -0.57, 0.86 ]
Parnetti 1985
18
2.2 (7.6)
18
0.7 (6.9)
54.6 %
0.20 [ -0.45, 0.86 ]
Total (95% CI)
32
100.0 %
0.18 [ -0.31, 0.66 ]
34
Heterogeneity: Chi2 = 0.01, df = 1 (P = 0.91); I2 =0.0%
Test for overall effect: Z = 0.71 (P = 0.48)
Test for subgroup differences: Not applicable
-4
-2
Favours placebo
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
0
2
4
Favours piracetam
33
Analysis 1.3. Comparison 1 Cognition - Piracetam versus Control, Outcome 3 MMSE.
Review:
Piracetam for dementia or cognitive impairment
Comparison: 1 Cognition - Piracetam versus Control
Outcome: 3 MMSE
Study or subgroup
Piracetam
Mean
Difference
Placebo
N
Mean(SD)
N
Mean(SD)
Croisile 1993
14
-1.1 (6.9)
16
-2.9 (7.3)
Total (95% CI)
14
Weight
IV,Fixed,95% CI
Mean
Difference
IV,Fixed,95% CI
16
100.0 %
1.80 [ -3.29, 6.89 ]
100.0 %
1.80 [ -3.29, 6.89 ]
Heterogeneity: not applicable
Test for overall effect: Z = 0.69 (P = 0.49)
Test for subgroup differences: Not applicable
-10
-5
0
Favours placebo
5
10
Favours piracetam
Analysis 1.4. Comparison 1 Cognition - Piracetam versus Control, Outcome 4 Delayed memory continuous.
Review:
Piracetam for dementia or cognitive impairment
Comparison: 1 Cognition - Piracetam versus Control
Outcome: 4 Delayed memory continuous
Study or subgroup
Piracetam
Std.
Mean
Difference
Placebo
Weight
IV,Fixed,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Fixed,95% CI
Croisile 1993
14
-0.64 (4.42)
16
-1.77 (3.95)
45.2 %
0.26 [ -0.46, 0.98 ]
Parnetti 1985
18
1.1 (3.91)
18
0.6 (3.91)
54.8 %
0.13 [ -0.53, 0.78 ]
Total (95% CI)
32
100.0 %
0.19 [ -0.30, 0.67 ]
34
Heterogeneity: Chi2 = 0.08, df = 1 (P = 0.78); I2 =0.0%
Test for overall effect: Z = 0.76 (P = 0.45)
Test for subgroup differences: Not applicable
-4
-2
Favours piracetam
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
0
2
4
Favours placebo
34
Analysis 1.5. Comparison 1 Cognition - Piracetam versus Control, Outcome 5 Aphasia test.
Review:
Piracetam for dementia or cognitive impairment
Comparison: 1 Cognition - Piracetam versus Control
Outcome: 5 Aphasia test
Study or subgroup
Piracetam
Mean
Difference
Placebo
N
Mean(SD)
N
Mean(SD)
Croisile 1993
14
-1.74 (5.2)
16
-4.4 (7.9)
Total (95% CI)
14
Weight
Mean
Difference
100.0 %
2.66 [ -2.07, 7.39 ]
100.0 %
2.66 [ -2.07, 7.39 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
16
Heterogeneity: not applicable
Test for overall effect: Z = 1.10 (P = 0.27)
Test for subgroup differences: Not applicable
-10
-5
0
5
Favours piracetam
10
Favours placebo
Analysis 2.1. Comparison 2 Global Scales Piracetam versus Control, Outcome 1 Global Scales - Continuous.
Review:
Piracetam for dementia or cognitive impairment
Comparison: 2 Global Scales Piracetam versus Control
Outcome: 1 Global Scales - Continuous
Study or subgroup
Piracetam
Std.
Mean
Difference
Placebo
Weight
IV,Fixed,95% CI
Std.
Mean
Difference
N
Mean(SD)
N
Mean(SD)
IV,Fixed,95% CI
Diesfeldt 1978
3
-0.07 (1.37)
5
-0.3 (1.92)
39.0 %
0.11 [ -1.32, 1.55 ]
Pierlovisi 1991a
6
0.05 (13.6)
6
-6.57 (18.5)
61.0 %
0.38 [ -0.77, 1.52 ]
100.0 %
0.27 [ -0.62, 1.17 ]
1 Global Scale
Subtotal (95% CI)
9
11
Heterogeneity: Chi2 = 0.08, df = 1 (P = 0.78); I2 =0.0%
Test for overall effect: Z = 0.60 (P = 0.55)
Test for subgroup differences: Not applicable
-4
-2
Favours placebo
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
0
2
4
Favours piracetam
35
Analysis 2.2. Comparison 2 Global Scales Piracetam versus Control, Outcome 2 Global Impression of
Change.
Review:
Piracetam for dementia or cognitive impairment
Comparison: 2 Global Scales Piracetam versus Control
Outcome: 2 Global Impression of Change
Study or subgroup
Peto
Odds Ratio
Weight
Peto
Odds Ratio
Piracetam
Placebo
n/N
n/N
Hermann 1987
54/65
18/65
32.0 %
9.25 [ 4.64, 18.41 ]
Kretschmar 1976
27/39
12/39
19.5 %
4.57 [ 1.89, 11.03 ]
Macchione 1976
81/112
39/70
38.5 %
2.09 [ 1.11, 3.91 ]
Trabant 1977
10/20
13/20
9.9 %
0.55 [ 0.16, 1.90 ]
Total (95% CI)
236
194
100.0 %
3.43 [ 2.32, 5.07 ]
Peto,Fixed,95% CI
Peto,Fixed,95% CI
Total events: 172 (Piracetam), 82 (Placebo)
Heterogeneity: Chi2 = 19.17, df = 3 (P = 0.00025); I2 =84%
Test for overall effect: Z = 6.20 (P < 0.00001)
Test for subgroup differences: Not applicable
0.1 0.2
0.5
1
Favours placebo
2
5
10
Favours piracetam
Analysis 3.1. Comparison 3 Dependency - Piracetam versus Control, Outcome 1 Dependency Scale.
Review:
Piracetam for dementia or cognitive impairment
Comparison: 3 Dependency - Piracetam versus Control
Outcome: 1 Dependency Scale
Study or subgroup
Piracetam
Std.
Mean
Difference
Weight
Std.
Mean
Difference
3.44 (6.4)
79.8 %
-0.31 [ -1.03, 0.41 ]
2.18 (9.96)
20.2 %
-0.17 [ -1.60, 1.27 ]
100.0 %
-0.28 [ -0.93, 0.37 ]
Placebo
N
Mean(SD)
N
Mean(SD)
Croisile 1993
14
1.5 (5.8)
16
Diesfeldt 1978
3
0.57 (2.82)
5
Total (95% CI)
17
IV,Fixed,95% CI
IV,Fixed,95% CI
21
Heterogeneity: Chi2 = 0.03, df = 1 (P = 0.87); I2 =0.0%
Test for overall effect: Z = 0.85 (P = 0.40)
Test for subgroup differences: Not applicable
-4
-2
Favours placebo
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
0
2
4
Favours piracetam
36
Analysis 4.1. Comparison 4 Depression scales - Piracetam versus Control, Outcome 1 Depression Scales Continuous.
Review:
Piracetam for dementia or cognitive impairment
Comparison: 4 Depression scales - Piracetam versus Control
Outcome: 1 Depression Scales - Continuous
Study or subgroup
Piracetam
Mean
Difference
Placebo
N
Mean(SD)
N
Mean(SD)
Croisile 1993
14
-0.64 (10.2)
16
-2.1 (6.6)
Total (95% CI)
14
Weight
Mean
Difference
100.0 %
1.46 [ -4.79, 7.71 ]
100.0 %
1.46 [ -4.79, 7.71 ]
IV,Fixed,95% CI
IV,Fixed,95% CI
16
Heterogeneity: not applicable
Test for overall effect: Z = 0.46 (P = 0.65)
Test for subgroup differences: Not applicable
-10
-5
Favours placebo
0
5
10
Favours piracetam
APPENDICES
Appendix 1. Pre-publication search: December 2011
Source
Search strategy
1. ALOIS (www.medicine.ox.ac.uk/alois)
Advanced search: (Study aim: Treatment 52 (all dates)
dementia OR Treatment MCI) AND
(Study design: RCT) AND (Intervention:
piracetam OR nootropic OR “2-Oxo-1pyrrolidine” OR Lucetam OR Nootropil
OR Breinox)
2. MEDLINE In-process and other non- 1. exp Piracetam/
indexed citations and MEDLINE 1950- 2. piracetam.mp.
present (Ovid SP)
3. nootropic.mp.
4. 2-Oxo-1-pyrrolidine.mp.
5. or/1-4
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hits retrieved
190
37
(Continued)
6. exp Dementia/
7. Dementia, Multi-Infarct/
8. Dementia, Vascular/
9. Alzheimer Disease/
10. Lewy Body Disease/
11. Delirium/
12. Huntington Disease/
13. “Pick Disease of the Brain”/
14. Kluver-Bucy Syndrome/
15. Wernicke Encephalopathy/
16. Creutzfeldt-Jakob Syndrome/
17. Delirium, Dementia, Amnestic, Cognitive Disorders/
18. dement*.mp.
19. Alzheimer*.mp.
20. (lewy* and bod*).mp.
21. deliri*.mp.
22. ((cognit* or memory* or mental*) adj3
(degenerat* or declin* or impair* or los* or
deteriorat*)).mp
23. (chronic and cerebrovascular).mp.
24. (“organic brain disease” or “organic
brain syndrome”).mp
25. “supranuclear palsy”.mp.
26. (“normal pressure hydrocephalus” and
“shunt*”).mp.
27. “benign senescent forgetfulness”.mp.
28. (cerebr* and deteriorat*).mp.
29. (cerebral* and insufficient*).mp.
30. (confusion* or confused).mp.
31. (pick* adj2 disease).mp.
32. (creutzfeldt or jcd or cjd).mp.
33. huntington*.mp.
34. binswanger*.mp.
35. korsako*.mp.
36. (mci or “subjective memory complaint”
or “episodic memory”).mp
37. (“incipient dementia” or “pre-clinical
ad” or “pre-clinical alzheimer*”).mp
38. (ARCD or ACMI or SMC or CIND
or BSF or AAMI or LCD or AACD or
MNCD or MCD).mp
39. (“n-mci” or “a-mci” or “m-mci”).mp.
40. or/6-39
41. 5 and 40
42. randomized controlled trial.pt.
43. controlled clinical trial.pt.
44. randomized.ab.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
38
(Continued)
45. placebo.ab.
46. drug therapy.fs.
47. randomly.ab.
48. trial.ab.
49. groups.ab.
50. or/42-49
51. (animals not (humans and animals)).
sh.
52. 50 not 51
53. 52 and 41
3. EMBASE
1974-2011 Dec 5 (Ovid SP)
1. exp piracetam/
79
2. piracetam.mp.
3. nootropic.mp.
4. 2-Oxo-1-pyrrolidine.mp.
5. or/1-4
6. exp dementia/
7. exp multiinfarct dementia/
8. exp Alzheimer disease/
9. diffuse Lewy body disease/
10. delirium/
11. exp Huntington chorea/
12. Pick presenile dementia/
13. Kluver Bucy syndrome/
14. Wernicke encephalopathy/
15. Creutzfeldt Jakob disease/
16. cognitive defect/
17. dement*.mp.
18. Alzheimer*.mp.
19. (lewy* and bod*).mp.
20. deliri*.mp.
21. ((cognit* or memory* or mental*) adj3
(degenerat* or declin* or impair* or los* or
deteriorat*)).mp
22. (chronic adj2 cerebrovascular).mp.
23. (“organic brain disease” or “organic
brain syndrome”).mp
24. “supranuclear palsy”.mp.
25. (“normal pressure hydrocephalus” and
“shunt*”).mp.
26. “benign senescent forgetfulness”.mp.
27. (cerebr* adj deteriorat*).mp.
28. (pick* adj2 disease).mp.
29. (creutzfeldt or jcd or cjd).mp.
30. huntington*.mp.
31. binswanger*.mp.
32. (mci or “subjective memory complaint”
or “episodic memory”).mp
33. (“incipient dementia” or “pre-clinical
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
39
(Continued)
ad” or “pre-clinical alzheimer*”).mp
34. (ARCD or ACMI or SMC or CIND
or BSF or AAMI or LCD or AACD or
MNCD or MCD).mp
35. (“n-mci” or “a-mci” or “m-mci”).mp.
36. or/6-35
37. 36 and 5
38. randomized controlled trial/
39. controlled clinical trial/
40. random*.ti,ab.
41. placebo.ti,ab.
42. “double-blind*”.mp.
43. “control group”.mp.
44. trial.ti,ab.
45. or/38-44
46. 45 and 37
47. (2010* or 2011*).em.
48. 46 and 47
4. PSYCINFO
1806-December week 2 2011 (Ovid SP)
1. exp Piracetam/
14
2. piracetam.mp.
3. nootropic.mp.
4. 2-Oxo-1-pyrrolidine.mp.
5. or/1-4
6. exp Dementia/
7. Vascular Dementia/
8. Alzheimers Disease/
9. Dementia with Lewy Bodies/
10. Delirium/
11. Huntingtons Disease/
12. Picks Disease/
13. Kluver Bucy Syndrome/
14. Wernickes Syndrome/
15. Creutzfeldt Jakob Syndrome/
16. dement*.mp.
17. Alzheimer*.mp.
18. (lewy* and bod*).mp.
19. deliri*.mp.
20. ((cognit* or memory* or mental*) adj3
(degenerat* or declin* or impair* or los* or
deteriorat*)).mp
21. (chronic and cerebrovascular).mp.
22. (“organic brain disease” or “organic
brain syndrome”).mp
23. “supranuclear palsy”.mp.
24. (“normal pressure hydrocephalus” and
“shunt*”).mp.
25. “benign senescent forgetfulness”.mp.
26. (cerebr* and deteriorat*).mp.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
40
(Continued)
27. (cerebral* and insufficient*).mp.
28. (confusion* or confused).mp.
29. (pick* adj2 disease).mp.
30. (creutzfeldt or jcd or cjd).mp.
31. huntington*.mp.
32. binswanger*.mp.
33. korsako*.mp.
34. (mci or “subjective memory complaint”
or “episodic memory”).mp
35. (“incipient dementia” or “pre-clinical
ad” or “pre-clinical alzheimer*”).mp
36. (ARCD or ACMI or SMC or CIND
or BSF or AAMI or LCD or AACD or
MNCD or MCD).mp
37. (“n-mci” or “a-mci” or “m-mci”).mp.
38. or/6-37
39. 5 and 38
40. random*.ti,ab.
41. Clinical Trials/
42. Drug Therapy/
43. “double-blind*”.ti,ab.
44. “control group”.mp.
45. or/40-44
46. 39 and 45
47. (2010* or 2011*).up.
48. 46 and 47
5. CINAHL (EBSCOhost)
S1 (MH “Dementia+”)
S2 (MH “Delirium”) or (MH “Delirium, Dementia, Amnestic, Cognitive Disorders”)
S3 (MH “Wernicke’s Encephalopathy”)
S4 TX dement*
S5 TX alzheimer*
S6 TX lewy* N2 bod*
S7 TX deliri*
S8 TX chronic N2 cerebrovascular
S9 TX “organic brain disease” or “organic
brain syndrome”
S10 TX “normal pressure hydrocephalus”
and “shunt*”
S11 TX “benign senescent forgetfulness”
S12 TX cerebr* N2 deteriorat*
S13 TX cerebral* N2 insufficient*
S14 TX pick* N2 disease
S15 TX creutzfeldt or jcd or cjd
S16 TX huntington*
S17 TX binswanger*
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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(Continued)
S18 TX korsako*
S19 S1 or S2 or S3 or S4 or S5 or S6 or S7
or S8 or S9 or S10 or S11 or S12 or S13 or
S14 or S15 or S16 or S17 or S18
S20 TX “cognit* impair*”
S21 TX “cognit* defect*”
S22 (MH “Cognition Disorders+”)
S23 TX MCI
S24 TX ACMI
S25 TX ARCD
S26 TX SMC
S27 TX CIND
S28 TX BSF
S29 TX AAMI
S30 AB MD
S31 AB LCD
S32 AB QD OR “questionable dementia”
S33 TX AACD
S34 TX MNCD
S35 TX “N-MCI” or “A-MCI” or “MMCI”
S36 TX “preclinical AD”
S37 TX “pre-clinical AD”
S38 TX “preclinical alzheimer*” or “preclinical alzheimer*”
S39 TX aMCI OR MCIa
S40 TX “CDR 0.5” or “clinical dementia
rating scale 0.5”
S41 TX “GDS 3” OR “stage 3 GDS”
S42 TX “global deterioration scale” AND
“stage 3”
S43 TX “Benign senescent forgetfulness”
S44 TX “mild neurocognit* disorder*”
S45 TX prodrom* N2 dement*
S46 TX “age-related symptom*”
S47 TX cognit* N2 deficit*
S48 TX cognit* N2 deteriorat*
S49 TX cognit* N2 declin*
S50 TX cognit* N2 degenerat*
S51 TX cognit* N2 complain*
S52 TX cognit* N2 disturb*
S53 TX cognit* N2 disorder*
S54 TX memory N2 episod* or TX memory N2 los* or TX memory N2 impair* or
TX memory N2 complain*
S55 TX memory N2 disturb* or TX memory N2 disorder* or TX cerebr* N2 impair*
or TX cerebr* N2 los*
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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(Continued)
S56 TX cerebr* N2 complain* or TX
cerebr* N2 deteriorat* or TX cerebr* N2
disorder* or TX cerebr* N2 disturb*
S57 TX mental* N2 declin* or TX mental*
N2 los* or TX mental* N2 impair* or TX
mental* N2 deteriorat*
S58 TX “pre-clinical dementia” or TX “preclinical dementia”
S59 S20 or S21 or S22 or S23 or S24 or
S25 or S26 or S27 or S28 or S29 or S30 or
S31 or S32 or S33 or S34 or S35 or S36 or
S37 or S38 or S39 or S40 or S41 or S42 or
S43 or S44 or S45 or S46 or S47 or S48 or
S49 or S50 or S51 or S52 or S53 or S54 or
S55 or S56 or S57 or S58
S60 S19 or S59
6. Web of Science (1945-present) and con- Topic=(piracetam* OR nootropic OR 17
ference proceedings
“2-Oxo-1-pyrrolidine” OR Lucetam OR
Nootropil OR Breinox) AND Topic=(dementia* OR alzheimer* OR BPSD OR
lewy OR “cognit* impair*” OR MCI OR
VCI OR AD) AND Topic=(randomly OR
placebo OR groups OR trial OR RCT OR
randomized OR randomised) AND Year
Published=(2010-2011)
Timespan=All
Years.
Databases=
SCI-EXPANDED, SSCI, A&HCI, CPCIS, CPCI-SSH
Lemmatization=On
7. LILACS (BIREME)
piracetam OR nootropic OR “2-Oxo-1- 39 (all dates)
pyrrolidine” OR Lucetam OR Nootropil
OR Breinox
8. CENTRAL (The Cochrane Library) (Is- #1 MeSH descriptor Piracetam explode all 26
sue 4 of 4, Oct 2010)
trees
#2 piracetam
#3 nootropic
#4 2-Oxo-1-pyrrolidine
#5 (#1 OR #2 OR #3 OR #4)
#6 MeSH descriptor Dementia explode all
trees
#7 MeSH descriptor Dementia, Multi-Infarct explode all trees
#8 MeSH descriptor Dementia, Vascular
explode all trees
#9 MeSH descriptor Alzheimer Disease exPiracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
43
(Continued)
plode all trees
#10 MeSH descriptor Lewy Body Disease
explode all trees
#11 MeSH descriptor Delirium explode all
trees
#12 MeSH descriptor Huntington Disease
explode all trees
#13 MeSH descriptor Pick Disease of the
Brain explode all trees
#14 MeSH descriptor Kluver-Bucy Syndrome explode all trees
#15 MeSH descriptor Wernicke Encephalopathy explode all trees
#16 MeSH descriptor Creutzfeldt-Jakob
Syndrome explode all trees
#17 MeSH descriptor Delirium, Dementia, Amnestic, Cognitive Disorders explode
all trees
#18 dement*
#19 Alzheimer*
#20 lewy* and bod*
#21 deliri*
#22 (cognit* or memory* or mental*) adj3
(degenerat* or declin* or impair* or los* or
deteriorat*)
#23 chronic and cerebrovascular
#24 “organic brain disease” or “organic
brain syndrome”
#25 “supranuclear palsy”
#26 “normal pressure hydrocephalus” and
“shunt*”
#27 “benign senescent forgetfulness”
#28 cerebr* adj4 deteriorat*
#29 cerebral* adj4 insufficient*
#30 pick* adj2 disease
#31 creutzfeldt or jcd or cjd
#32 huntington*
#33 binswanger*
#34 korsako*
#35 mci or “subjective memory complaint”
or “episodic memory”
#36 “incipient dementia” or “pre-clinical
ad” or “pre-clinical alzheimer*”
#37 ARCD or ACMI or SMC or CIND
or BSF or AAMI or LCD or AACD or
MNCD or MCD
#38 “n-mci” or “a-mci” or “m-mci”
#39 (#6 OR #7 OR #8 OR #9 OR #10
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
44
(Continued)
OR #11 OR #12 OR #13 OR #14 OR #
15 OR #16 OR #17 OR #18 OR #19 OR
#20 OR #21 OR #22 OR #23 OR #24
OR #25 OR #26 OR #27 OR #28 OR #
29 OR #30 OR #31 OR #32 OR #33 OR
#34 OR #35 OR #36 OR #37 OR #38)
#40 (#5 AND #39), from 2010 to 2011
9.
Clinicaltrials.gov
www.clinicaltrials.gov)
( Interventional Studies | memory OR de- 8
mentia OR alzheimer OR alzheimers
OR lewy OR cognition OR cognitive |
Nootropil OR piracetam OR Lucetam OR
Breinox OR 2-Oxo-1-pyrrolidine
10. ICTRP Search Portal (http:/ piracetam OR nootropic OR 2-Oxo-1- 18 (all dates)
/apps.who.int/trialsearch) [includes: Aus- pyrrolidine OR Lucetam OR Nootropil
tralian New Zealand Clinical Trials Reg- OR Breinox
istry; ClinicalTrilas.gov; ISRCTN; Chinese
Clinical Trial Registry; Clinical Trials Registry - India; Clinical Research Information Service - Republic of Korea; German
Clinical Trials Register; Iranian Registry
of Clinical Trials; Japan Primary Registries
Network; Pan African Clinical Trial Registry; Sri Lanka Clinical Trials Registry; The
Netherlands National Trial Register]
TOTAL before de-duplication
415
TOTAL after de-dupe and first-assess
5
Appendix 2. Update search: February 2010
Source
Search strategy
MEDLINE In-process and other non- 1. exp Piracetam/
indexed citations and MEDLINE 1950- 2. piracetam.mp.
present (Ovid SP)
3. nootropic.mp.
4. 2-Oxo-1-pyrrolidine.mp.
5. or/1-4
6. exp Dementia/
7. Dementia, Multi-Infarct/
8. Dementia, Vascular/
9. Alzheimer Disease/
10. Lewy Body Disease/
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hits
191
45
(Continued)
11. Delirium/
12. HuntingtonDisease/
13. “Pick Disease of the Brain”/
14. Kluver-Bucy Syndrome/
15. Wernicke Encephalopathy/
16. Creutzfeldt-Jakob Syndrome/
17. Delirium, Dementia, Amnestic, Cognitive Disorders/
18. dement*.mp.
19. Alzheimer*.mp.
20. (lewy* and bod*).mp.
21. deliri*.mp.
22. ((cognit* or memory* or mental*) adj3
(degenerat* or declin* or impair* or los* or
deteriorat*)).mp
23. (chronic and cerebrovascular).mp.
24. (“organic brain disease” or “organic
brain syndrome”).mp
25. “supranuclear palsy”.mp.
26. (“normal pressure hydrocephalus” and
“shunt*”).mp.
27. “benign senescent forgetfulness”.mp.
28. (cerebr* and deteriorat*).mp.
29. (cerebral* and insufficient*).mp.
30. (confusion* or confused).mp.
31. (pick* adj2 disease).mp.
32. (creutzfeldt or jcd or cjd).mp.
33. huntington*.mp.
34. binswanger*.mp.
35. korsako*.mp.
36. (mci or “subjective memory complaint”
or “episodic memory”).mp
37. (“incipient dementia” or “pre-clinical
ad” or “pre-clinical alzheimer*”).mp
38. (ARCD or ACMI or SMC or CIND
or BSF or AAMI or LCD or AACD or
MNCD or MCD).mp
39. (“n-mci” or “a-mci” or “m-mci”).mp.
40. or/6-39
41. 5 and 40
42. randomized controlled trial.pt.
43. controlled clinical trial.pt.
44. randomized.ab.
45. placebo.ab.
46. drug therapy.fs.
47. randomly.ab.
48. trial.ab.
49. groups.ab.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
46
(Continued)
50. or/42-49
51. (animals not (humans and animals)).
sh.
52. 50 not 51
53. 52 and 41
54. 200712*.ed.
55. 2008*.ed.
56. 2009*.ed.
57. 2010*.ed.
58. or/54-57
59. 53 and 58
EMBASE
1980-2010 week 7 (Ovid SP)
1. exp piracetam/
69
2. piracetam.mp.
3. nootropic.mp.
4. 2-Oxo-1-pyrrolidine.mp.
5. or/1-4
6. exp dementia/
7. exp multiinfarct dementia/
8. exp Alzheimer disease/
9. diffuse Lewy body disease/
10. delirium/
11. exp Huntingtonchorea/
12. Pick presenile dementia/
13. Kluver Bucy syndrome/
14. Wernicke encephalopathy/
15. Creutzfeldt Jakob disease/
16. cognitive defect/
17. dement*.mp.
18. Alzheimer*.mp.
19. (lewy* and bod*).mp.
20. deliri*.mp.
21. ((cognit* or memory* or mental*) adj3
(degenerat* or declin* or impair* or los* or
deteriorat*)).mp
22. (chronic adj2 cerebrovascular).mp.
23. (“organic brain disease” or “organic
brain syndrome”).mp
24. “supranuclear palsy”.mp.
25. (“normal pressure hydrocephalus” and
“shunt*”).mp.
26. “benign senescent forgetfulness”.mp.
27. (cerebr* adj deteriorat*).mp.
28. (pick* adj2 disease).mp.
29. (creutzfeldt or jcd or cjd).mp.
30. huntington*.mp.
31. binswanger*.mp.
32. (mci or “subjective memory complaint”
or “episodic memory”).mp
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
47
(Continued)
33. (“incipient dementia” or “pre-clinical
ad” or “pre-clinical alzheimer*”).mp
34. (ARCD or ACMI or SMC or CIND
or BSF or AAMI or LCD or AACD or
MNCD or MCD).mp
35. (“n-mci” or “a-mci” or “m-mci”).mp.
36. or/6-35
37. 36 and 5
38. randomized controlled trial/
39. controlled clinical trial/
40. random*.ti,ab.
41. placebo.ti,ab.
42. “double-blind*”.mp.
43. “control group”.mp.
44. trial.ti,ab.
45. or/38-44
46. 45 and 37
47. (2007* or 2008* or 2009* or 2010*).
em.
48. 46 and 47
PSYCINFO
1806-February week 3 2010 (Ovid SP)
1. exp Piracetam/
20
2. piracetam.mp.
3. nootropic.mp.
4. 2-Oxo-1-pyrrolidine.mp.
5. or/1-4
6. exp Dementia/
7. Vascular Dementia/
8. Alzheimers Disease/
9. Dementia with Lewy Bodies/
10. Delirium/
11. HuntingtonsDisease/
12. Picks Disease/
13. Kluver Bucy Syndrome/
14. Wernickes Syndrome/
15. Creutzfeldt Jakob Syndrome/
16. dement*.mp.
17. Alzheimer*.mp.
18. (lewy* and bod*).mp.
19. deliri*.mp.
20. ((cognit* or memory* or mental*) adj3
(degenerat* or declin* or impair* or los* or
deteriorat*)).mp
21. (chronic and cerebrovascular).mp.
22. (“organic brain disease” or “organic
brain syndrome”).mp
23. “supranuclear palsy”.mp.
24. (“normal pressure hydrocephalus” and
“shunt*”).mp.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
48
(Continued)
25. “benign senescent forgetfulness”.mp.
26. (cerebr* and deteriorat*).mp.
27. (cerebral* and insufficient*).mp.
28. (confusion* or confused).mp.
29. (pick* adj2 disease).mp.
30. (creutzfeldt or jcd or cjd).mp.
31. huntington*.mp.
32. binswanger*.mp.
33. korsako*.mp.
34. (mci or “subjective memory complaint”
or “episodic memory”).mp
35. (“incipient dementia” or “pre-clinical
ad” or “pre-clinical alzheimer*”).mp
36. (ARCD or ACMI or SMC or CIND
or BSF or AAMI or LCD or AACD or
MNCD or MCD).mp
37. (“n-mci” or “a-mci” or “m-mci”).mp.
38. or/6-37
39. 5 and 38
40. random*.ti,ab.
41. Clinical Trials/
42. Drug Therapy/
43. “double-blind*”.ti,ab.
44. “control group”.mp.
45. or/40-44
46. 39 and 45
47. (2007* or 2008* or 2009* or 2010*).
up.
48. 46 and 47
CINAHL (EBSCOhost)
S1 TX Piracetam
37
S2 (MH “Nootropic Agents”)
S3 TX 2-Oxo-1-pyrrolidine
S4 S1 or S2 or S3
S5 (MH “Dementia”) or (MH “Dementia,
Vascular”) or (MH “Delirium, Dementia,
Amnestic, Cognitive Disorders”) or (MH
“Dementia, Multi-Infarct”) or (MH “Dementia, Presenile”) or (MH “Dementia, Senile”)
S6 (MH “Alzheimer’s Disease”)
S7 TX “Lew* Bod*”
S8 (MH “Huntington’s Disease”)
S9 (MH “Pick Disease of the Brain”)
S10 (MH “Wernicke’s Encephalopathy”)
S11 (MH “Creutzfeldt-Jakob Syndrome”)
S12 TX dement*
S13 TX Alzheimer*
S14 TX “organic brain disease” or “organic
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
49
(Continued)
brain syndrome”
S15 TX “supranuclear palsy”
S16 TX “normal pressure hydrocephalus”
and “shunt*”
S17 TX “benign senescent forgetfulness”
S18 TX cerebr* and deteriorat*
S19 TX cerebral* and insufficient*
S20 TX “pick* disease”
S21 TX creutzfeldt or jcd or cjd
S22 TX huntington*
S23 TX binswanger*
S24 TX korsako*
S25 TX mci or “subjective memory complaint” or “episodic memory”
S26 TX “incipient dementia” or “pre-clinical ad” or “pre-clinical alzheimer*”
S27 TX ARCD or ACMI or SMC or
CIND or BSF or AAMI or LCD or AACD
or MNCD or MCD
S28 TX “n-mci” or “a-mci” or “m-mci”
S29 S5 or S6 or S7 or S8 or S9 or S10 or
S11 or S12 or S13 or S14 or S15 or S16 or
S17 or S18 or S19 or S20 or S21 or S22 or
S23 or S24 or S25 or S26 or S27 or S28
S30 S4 and S29
S31 TX random*
S32 TX placebo*
S33 TX trial*
S34 TX “control group”
S35 TX “double-blind*”
S36 (MH “Clinical Trials”)
S37 S31 or S32 or S33 or S34 or S35 or
S36
S38 S30 and S37
S39 EM 2007
S40 EM 2008
S41 EM 2009
S42 EM 2010
S43 S39 or S40 or S41 or S42
S44 S38 and S43
Web of Science with Conference Proceed- #1 Topic=(Piracetam OR “2-Oxo-1- 25
ings (1945 to present)
pyrrolidine” OR nootropic)
#2
Topic=(Dement*
OR alzheimer* OR “lew* bod*” OR huntington* OR creutzfeldt OR “pick* disease”
OR wenicke*)
#3 #2 AND #1
#4 Topic=(random* OR trial* OR placebo
OR “double-blind*” OR “control group”)
Piracetam for dementia or cognitive impairment (Review)
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(Continued)
#5 #4 AND #3
#6 Topic=(#5)
LILACS (BIREME)
Piracetam OR “2-Oxo-1-pyrrolidine”
ALOIS (www.medicine.ox.ac.uk/alois)
Advanced search: (Study Aim: Treatment 51
Dementia) AND (Study design: RCT)
AND (Intervention: piracetam)
Umin (Clinical Trial Register of Japan)
Piracetam OR 2-Oxo-1-pyrrolidine OR 0
nootropic
CENTRAL (The Cochrane Library)
#1 MeSH descriptor Piracetam explode all 58
trees
#2 piracetam
#3 nootropic
#4 2-Oxo-1-pyrrolidine
#5 (#1 OR #2 OR #3 OR #4)
#6 MeSH descriptor Dementia explode all
trees
#7 MeSH descriptor Dementia, Multi-Infarct explode all trees
#8 MeSH descriptor Dementia, Vascular
explode all trees
#9 MeSH descriptor Alzheimer Disease explode all trees
#10 MeSH descriptor Lewy Body Disease
explode all trees
#11 MeSH descriptor Delirium explode all
trees
#12 MeSH descriptor Huntington Disease
explode all trees
#13 MeSH descriptor Pick Disease of the
Brain explode all trees
#14 MeSH descriptor Kluver-Bucy Syndrome explode all trees
#15 MeSH descriptor Wernicke Encephalopathy explode all trees
#16 MeSH descriptor Creutzfeldt-Jakob
Syndrome explode all trees
#17 MeSH descriptor Delirium, Dementia, Amnestic, Cognitive Disorders explode
all trees
#18 dement*
#19 Alzheimer*
#20 lewy* and bod*
#21 deliri*
#22 (cognit* or memory* or mental*) adj3
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
17
51
(Continued)
(degenerat* or declin* or impair* or los* or
deteriorat*)
#23 chronic and cerebrovascular
#24 “organic brain disease” or “organic
brain syndrome”
#25 “supranuclear palsy”
#26 “normal pressure hydrocephalus” and
“shunt*”
#27 “benign senescent forgetfulness”
#28 cerebr* adj4 deteriorat*
#29 cerebral* adj4 insufficient*
#30 pick* adj2 disease
#31 creutzfeldt or jcd or cjd
#32 huntington*
#33 binswanger*
#34 korsako*
#35 mci or “subjective memory complaint”
or “episodic memory”
#36 “incipient dementia” or “pre-clinical
ad” or “pre-clinical alzheimer*”
#37 ARCD or ACMI or SMC or CIND
or BSF or AAMI or LCD or AACD or
MNCD or MCD
#38 “n-mci” or “a-mci” or “m-mci”
#39 (#6 OR #7 OR #8 OR #9 OR #10
OR #11 OR #12 OR #13 OR #14 OR #
15 OR #16 OR #17 OR #18 OR #19 OR
#20 OR #21 OR #22 OR #23 OR #24
OR #25 OR #26 OR #27 OR #28 OR #
29 OR #30 OR #31 OR #32 OR #33 OR
#34 OR #35 OR #36 OR #37 OR #38)
#40 (#5 AND #39), from 2007 to 2010
Clinicaltrials.gov
Advanced search: (Search term: Piracetam) 38
AND (date received: 10/01/2007 -02/22/
2010)
ICTRP Search Portal
Advanced search: (Intervention: Piracetam 3
OR 2-Oxo-1-pyrrolidine) AND (date received: 01/10/2007 - 22/02/2010)
Total
509
Total after first-assess and de-duplication by TSC
10
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
52
Appendix 3. Update search: December 2007
Source
Search strategy
Hits
CDCIG SR (now ALOIS)
piracetam OR nootropic OR 2-Oxo-1pyrrolidine
410
MEDLINE; EMBASE; CENTRAL; (all terms were searched as: title, abstract, 102
PsycINFO; CINAHL (all via Ovid SP)
keyword, controlled vocabulary)
piracetam OR nootropic OR 2-Oxo-1pyrrolidine
AND
(((Dementia OR Alzheimer$ OR (Lewy
body) OR arteriosclerosis OR (Huntington disease) OR (Kluver Bucy) OR (Pick
disease) OR delirium OR (cerebrovascular disorder$) OR (Wernicke encephalopathy) OR (Korsakoff psychosis) OR ((cognit$ or memory$ or mental$) AND (declin$ or impair$ or los$ or deteriorat$)) OR
(cerebr$ deteriorat$) OR (cerebr$ insufficien$)
AND
Phases 1-3 of the
Highly sensitive search strategies for identifying reports of randomized controlled trials in Medline (APPENDIX 5b, Cochrane
Handbook, 2006), all terms searched as Title, abstract, keyword, Publication type
LILACs (BIREME)
piracetam OR nootropic OR 2-Oxo-1- 0
pyrrolidine
AND
(LILACS search strategy from “Dementia
Group Search strategy for Specialized Register for dementia terms. No trials terms
were used)
WHAT’S NEW
Last assessed as up-to-date: 3 January 2012.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
53
Date
Event
Description
4 December 2011
New search has been performed
A pre-publication search was performed for this review on 4 December 2011.
No new studies for inclusion were identified from this search
12 February 2010
New search has been performed
An update search was performed for this review on 12 February 2010. One
new study was for inclusion
HISTORY
Protocol first published: Issue 2, 1996
Review first published: Issue 2, 1998
Date
Event
Description
14 April 2008
New search has been performed
The update search of 17 December 2007 retrieved one
study, Szalma 2006, that has been excluded
23 August 2005
New search has been performed
Minor update of review resulting from update search of
May 2005
6 November 2003
New citation required and conclusions have changed
Substantive amendment
CONTRIBUTIONS OF AUTHORS
The original search was performed in 1997. LF performed the search.
In November 2000, the CDCIG office re-ran the search strategy but no new studies were identified for inclusion. Two further duplicate
publications of the Israel 1994 study were identified and 14 other new studies were identified and were added to the exclusion list.
These studies were rated by a single review author (JGE). There were no substantial changes made to the text of the review.
CDCIG Contact editor: Jenny McCleery
DECLARATIONS OF INTEREST
None known.
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
54
NOTES
In November 2000 the CDCIG office ran the search strategy again but no new studies were identified for inclusion. Two further
duplicate publications of the Israel 1994 study were identified and 14 other new studies were identified and were added to the exclusion
list. These studies were rated by a single review author (JGE). There were no substantial changes made to the text of the review.
In May 2001, the background section of the abstract was added and the main background section was rewritten.
In 2002, a review of piracetam by employees and consultants of the pharmaceutical company manufacturing piracetam was published.
These reviewers had access to unpublished company reports held by the manufacturers. Despite repeated requests the company has
not made the data of these, and any other internal reports that may exist, available to us. The findings of the Company review were,
however, similar to ours.
INDEX TERMS
Medical Subject Headings (MeSH)
Alzheimer Disease [drug therapy]; Cognition Disorders [∗ drug therapy]; Cross-Over Studies; Dementia [∗ drug therapy]; Nootropic
Agents [∗ therapeutic use]; Piracetam [∗ therapeutic use]
MeSH check words
Humans
Piracetam for dementia or cognitive impairment (Review)
Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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