Piracetam for dementia or cognitive impairment

Leon Flicker; John Grimley Evans

doi:10.1002/14651858.CD001011

. 2004 Jan 26;2004(1):CD001011. doi: 10.1002/14651858.CD001011

Piracetam for dementia or cognitive impairment

Leon Flicker ^1,^✉, John Grimley Evans ²

Editor: Cochrane Dementia and Cognitive Improvement Group

PMCID: PMC12016011

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review by employees and consultants of the manufacturing company, UCB Pharma (Waegemans 2002) which included data from unpublished studies not made available to Cochrane review authors.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 The pharmaceutical company marketing piracetam did not release the results of several unpublished trials.

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.

Keywords: Humans, Alzheimer Disease, Alzheimer Disease/drug therapy, Cognition Disorders, Cognition Disorders/drug therapy, Cross‐Over Studies, Dementia, Dementia/drug therapy, Nootropic Agents, Nootropic Agents/therapeutic use, Piracetam, Piracetam/therapeutic use

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.

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 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.

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 piracetam 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.

Age
Sex
Severity of dementia at baseline
Dose
Duration of treatment
Criteria used for diagnosis

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 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.

Types of interventions

Piracetam at any dose with concomitant parallel placebo control group for longer than one day of treatment.

Types of outcome measures

The primary outcomes of interest were:

dependency;
global impression;
functional performance;
behavioral disturbance;
quality of life;
cognitive function (as measured by psychometric tests);
effect on carer;
death;
acceptability of treatment as measured by withdrawal from trial;
safety as measured by the incidence of adverse effects (including side‐effects) leading to withdrawal; and
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.

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.

Monthly searches of a number of major healthcare databases: MEDLINE, EMBASE, CINAHL, PsycINFO and LILACS.
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).
Quarterly search of The Cochrane Library’s Central Register of Controlled Trials (CENTRAL).
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.

Inclusion criteria

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.

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 follow‐up.

Studies may have included a titration period prior to the randomization phase of the study. We did not use data from these non‐randomized titration periods to assess safety or efficacy since participants were usually not randomized, nor were treatment or dose allocations concealed.

Data analysis

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.

Age (> 65 years versus ≦ 65 years).
Sex (male vs female).
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).
Dose.
Duration of treatment.

Results

Description of 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 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 NINCDS‐ADRDA 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.

2.2 — Comparison 2 Global Scales Piracetam versus Control, Outcome 2 Global Impression of Change.

The evidence of effects on cognition and other measures, was inconclusive. In the limited data available, no significant differences were found between treatment and placebo groups for cognition (immediate memory, visuospatial, MMSE, delayed memory or speech) for dependency, or for depression.

Discussion

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.

Authors' conclusions

Implications for practice.

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.

Implications for research.

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.

The potential use of this drug could be further evaluated by the following methods.

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.
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.

What's new

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.

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

Source	Search strategy	Hits retrieved
1. ALOIS (www.medicine.ox.ac.uk/alois)	Advanced search: (Study aim: Treatment dementia OR Treatment MCI) AND (Study design: RCT) AND (Intervention: piracetam OR nootropic OR "2‐Oxo‐1‐pyrrolidine" OR Lucetam OR Nootropil OR Breinox)	52 (all dates)
2. MEDLINE In‐process and other non‐indexed citations and MEDLINE 1950‐present (Ovid SP)	1. exp Piracetam/ 2. piracetam.mp. 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/ 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. 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	190
3. EMBASE 1974‐2011 Dec 5 (Ovid SP)	1. exp piracetam/ 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 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	79
4. PSYCINFO 1806‐December week 2 2011 (Ovid SP)	1. exp Piracetam/ 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. 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	14
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* 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 "M‐MCI" S36 TX "preclinical AD" S37 TX "pre‐clinical AD" S38 TX "preclinical alzheimer" or "pre‐clinical 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* 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 conference proceedings	Topic=(piracetam* OR nootropic OR "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, CPCI‐S, CPCI‐SSH. Lemmatization=On	17
7. LILACS (BIREME)	piracetam OR nootropic OR "2‐Oxo‐1‐pyrrolidine" OR Lucetam OR Nootropil OR Breinox	39 (all dates)
8. CENTRAL (The Cochrane Library) (Issue 4 of 4, Oct 2010)	#1 MeSH descriptor Piracetam explode all 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 (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 2010 to 2011	26
9. Clinicaltrials.gov (www.clinicaltrials.gov)	Interventional Studies \| memory OR dementia OR alzheimer OR alzheimers OR lewy OR cognition OR cognitive \| Nootropil OR piracetam OR Lucetam OR Breinox OR 2‐Oxo‐1‐pyrrolidine	8
10. ICTRP Search Portal (http://apps.who.int/trialsearch) [includes: Australian New Zealand Clinical Trials Registry; 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]	piracetam OR nootropic OR 2‐Oxo‐1‐pyrrolidine OR Lucetam OR Nootropil OR Breinox	18 (all dates)
TOTAL before de‐duplication		415
TOTAL after de‐dupe and first‐assess		5

Source	Search strategy	Hits
MEDLINE In‐process and other non‐indexed citations and MEDLINE 1950‐present (Ovid SP)	1. exp Piracetam/ 2. piracetam.mp. 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/ 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. 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	191
EMBASE 1980‐2010 week 7 (Ovid SP)	1. exp piracetam/ 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. 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	69
PSYCINFO 1806‐February week 3 2010 (Ovid SP)	1. exp Piracetam/ 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. 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	20
CINAHL (EBSCOhost)	S1 TX Piracetam 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 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	37
Web of Science with Conference Proceedings (1945 to present)	#1 Topic=(Piracetam OR "2‐Oxo‐1‐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") #5 #4 AND #3 #6 Topic=(#5)	25
LILACS (BIREME)	Piracetam OR “2‐Oxo‐1‐pyrrolidine”	17
ALOIS (www.medicine.ox.ac.uk/alois)	Advanced search: (Study Aim: Treatment Dementia) AND (Study design: RCT) AND (Intervention: piracetam)	51
Umin (Clinical Trial Register of Japan)	Piracetam OR 2‐Oxo‐1‐pyrrolidine OR nootropic	0
CENTRAL (The Cochrane Library)	#1 MeSH descriptor Piracetam explode all 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 (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	58
Clinicaltrials.gov	Advanced search: (Search term: Piracetam) AND (date received: 10/01/2007 ‐02/22/2010)	38
ICTRP Search Portal	Advanced search: (Intervention: Piracetam OR 2‐Oxo‐1‐pyrrolidine) AND (date received: 01/10/2007 ‐ 22/02/2010)	3
Total		509
Total after first‐assess and de‐duplication by TSC		10

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Immediate Memory Tests Continuous	3	78	Std. Mean Difference (IV, Fixed, 95% CI)	0.25 [‐0.20, 0.70]
2 Visuospatial	2	66	Std. Mean Difference (IV, Fixed, 95% CI)	0.18 [‐0.31, 0.66]
3 MMSE	1	30	Mean Difference (IV, Fixed, 95% CI)	1.8 [‐3.29, 6.89]
4 Delayed memory continuous	2	66	Std. Mean Difference (IV, Fixed, 95% CI)	0.19 [‐0.30, 0.67]
5 Aphasia test	1	30	Mean Difference (IV, Fixed, 95% CI)	2.66 [‐2.07, 7.39]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Global Scales ‐ Continuous	2		Std. Mean Difference (IV, Fixed, 95% CI)	Subtotals only
1.1 Global Scale	2	20	Std. Mean Difference (IV, Fixed, 95% CI)	0.27 [‐0.62, 1.17]
2 Global Impression of Change	4	430	Peto Odds Ratio (Peto, Fixed, 95% CI)	3.43 [2.32, 5.07]

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

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	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

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

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

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

Source	Search strategy	Hits
CDCIG SR (now ALOIS)	piracetam OR nootropic OR 2‐Oxo‐1‐ pyrrolidine	410
MEDLINE; EMBASE; CENTRAL; PsycINFO; CINAHL (all via Ovid SP)	(all terms were searched as: title, abstract, keyword, controlled vocabulary). piracetam OR nootropic OR 2‐Oxo‐1‐pyrrolidine 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	102
LILACs (BIREME)	piracetam OR nootropic OR 2‐Oxo‐1‐pyrrolidine AND (LILACS search strategy from “Dementia Group Search strategy for Specialized Register for dementia terms. No trials terms were used)	0

Methods	Double‐blind, randomized trial.   3 randomized parallel groups which were then given a memory training program in a cross‐over 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

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*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

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

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)
Notes
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Allocation concealment (selection bias)	Low risk	A ‐ Adequate

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

Methods	Two studies reported in this paper. The first study is a randomized, double‐blind, placebo‐controlled, 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

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
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

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

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.
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.
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.
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.

PERMALINK

Piracetam for dementia or cognitive impairment

Leon Flicker

John Grimley Evans

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Inclusion criteria

Quality assessment

Data extraction

Data analysis

Results

Description of studies

Risk of bias in included studies

Effects of interventions

2.2. Analysis.

Discussion

Authors' conclusions

Implications for practice.

Implications for research.

What's new

History

Notes

Acknowledgements

Appendices

Appendix 1. Pre‐publication search: December 2011

Appendix 2. Update search: February 2010

Appendix 3. Update search: December 2007

Data and analyses

Comparison 1. Cognition ‐ Piracetam versus Control.

1.1. Analysis.

1.2. Analysis.

1.3. Analysis.

1.4. Analysis.

1.5. Analysis.

Comparison 2. Global Scales Piracetam versus Control.

2.1. Analysis.

Comparison 3. Dependency ‐ Piracetam versus Control.

3.1. Analysis.

Comparison 4. Depression scales ‐ Piracetam versus Control.

4.1. Analysis.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Chouinard 1983.

Croisile 1993.

Davidson 1987.

Diesfeldt 1978.

Fioravanti 1991.

Fleischhacker 1986.

Gainotti 1989.

Growdon 1985.

Gustafson 1978.

Hermann 1987.

Israel 1994.

Kretschmar 1976.

Lloyd‐Evans 1979.

Macchione 1976.

Mindus 1976.

Parnetti 1985.

Pierlovisi 1991a.

Pomara 1984.