Cytidinediphosphocholine (CDP choline) for cognitive and

behavioural disturbances associated with chronic cerebral

disorders in the elderly (Review)

Fioravanti M, Yanagi M

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2004, Issue 2
http://www.thecochranelibrary.com

Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the
elderly (Review)
Copyright © 2005 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the i
elderly (Review)
Copyright © 2005 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Cytidinediphosphocholine (CDP choline) for cognitive and

behavioural disturbances associated with chronic cerebral
disorders in the elderly

M Fioravanti1 , M Yanagi

1 Department of Psychiatric Science and Psychological Medicine, University of Rome “La Sapienza”, Rome, ITALY

Contact address:

Editorial group: Cochrane Dementia and Cognitive Improvement Group.

Publication status and date: Commented, published in Issue 1, 2005.

Citation: Fioravanti M, Yanagi M. Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated
with chronic cerebral disorders in the elderly. The Cochrane Database of Systematic Reviews , Issue . Art. No.: CD000269. DOI:
10.1002/14651858.CD000269.pub2.

Copyright © 2005 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

CDP-choline is used in the treatment of disorders of a cerebrovascular nature. The many years of its presence in the clinical field have
caused an evolution in dosage, method of administration, and selection criteria of patients to which the treatments was given. Modalities
of the clinical studies, including length of observation, severity of disturbance, and methodology of evaluation of the results were also
heterogeneous. In spite of uncertainties about its efficacy due to these complexities, CDP-choline is a frequently prescribed drug for
cognitive impairment in several European countries, especially when the clinical picture is predominantly one of cerebrovascular disease,
hence the need for this review.

Objectives

The objective is to assess the efficacy of CDP-choline (cytidinediphosphocholine) in the treatment of cognitive, emotional, and
behavioural deficits associated with chronic cerebral disorders in the elderly.

Search strategy

The trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement
Group on 20 January 2004 using the terms CDP-choline, CDP, citicolone, cytidine diphosphate choline or diphosphocholine. This
register contains records from all major health care databases and many ongoing trials databases and is updated regularly.

Selection criteria

All relevant unconfounded, double-blind, placebo-controlled, randomized trials of CDP-choline for cognitive impairment due to
chronic cerebral disorders are considered for inclusion in the review.

Data collection and analysis

Two reviewers independently reviewed the included studies, extracted the data, and pooled it when appropriate and possible. The
pooled odd ratios (95% CI) or the average differences (95% CI) were estimated. No intention-to-treat data were available from the
studies included.
Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the 1
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Main results

Seven of the included studies observed the subjects for a period between 20 to 30 days, one study was of 6 weeks duration, 4 studies
used cycles extending over 2 and 3 months and one study observed continuous administration over 3 months. The studies were
heterogeneous in dose, inclusion criteria for subjects, and outcome measures. Results are reported for the domains of attention, memory
testing, behavioural rating scales, global clinical impression and tolerability. There is no significant evidence of a beneficial effect of
CDP-choline on attention. There are significant beneficial effects of CDP-choline on memory function and behaviour. The drug is
well tolerated.

Authors’ conclusions

There is some evidence that CDP Choline has a positive effect on memory and behaviour in at least the short/medium term. The
evidence of benefit from global impression is stronger, but is still limited by the duration of the studies. Further research with CDP-
choline should focus on longer term studies in subjects who have been diagnosed with currently accepted standardised criteria, especially
vascular dementia.

PLAIN LANGUAGE SUMMARY

Synopsis

Some evidence that CDP Choline has a positive effect on memory and behaviour in at least the short/medium term in elderly people
with dementia associated with chronic cerebral disorders of the brain.

Patients with dementia associated with chronic cerebrovascular disorders do not usually respond to traditional anti-dementia treatments
in the same predictable and regular manner as can be observed in cases of Alzheimer’s dementia. There is some evidence that CDP-choline
provides some modest but consistent improvement of memory and behaviour in these patients. These findings, however, are limited
by the relatively short-term of clinical controlled observations, which never lasted more than three months. Subjective evaluations of
these patients as given by their doctors were consistently positive and no noticeable side effects were evidenced in the various studies
over the years.

BACKGROUND primary cognitive deterioration in groups of elderly patients who

CDP-choline (cytidine 5’-diphosphocholine) is a precursor essen- did not present with a primarily cerebrovascular pathology.
tial for the synthesis of phosphatidylcholine. Phosphatidylcholine
The prevalent use of this compound in the treatment of disorders
is one of the cell membrane components that is degraded during
of a cerebrovascular nature does not mean an homogeneous and
cerebral ischaemia to free fatty acids and free radicals, which are
consistent application of this therapy. Dosage, method of admin-
highly toxic. Animal studies suggest that CDP-Choline may pro-
istration, and selection criteria of patients vary. The modalities of
tect cell membranes by accelerating resynthesis of phospholipids.
the studies including length of observation, severity of disturbance,
CDP-choline may also attenuate the progression of ischaemic cell
and methodology of the evaluation of the results are also hetero-
damage by suppressing the release of free fatty acids.
geneous. In spite of these methodological difficulties in examin-
CDP-choline is a relatively old compound, developed and pro- ing its efficacy, CDP-choline is still a frequently prescribed drug
duced in Japan, originally used in the treatment of acute cere- for cognitive impairment in several European countries, especially
brovascular disorders. After being introduced in some of the Euro- when the clinical picture is predominantly one of cerebrovascular
pean markets, its use was progressively shifted from the treatment disease.
of acute to chronic cerebrovascular disorders. CDP-choline was
also sporadically prescribed as an adjuvant to L-Dopa treatment in
Parkinsonian patients. In some studies CDP-choline is used in the
treatment of primary degenerative dementia or of mild forms of OBJECTIVES
Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the 2
elderly (Review)
Copyright © 2005 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
The objective of this study is to evaluate the evidence for the clinical Clinical Global Impression
efficacy of CDP-choline for the symptoms of cognitive, emotional,
Clinical impression was evaluated in four studies with 217 subjects,
and behavioral impairment in older patients with dementia and
115 subjects in the CDP-choline group and 102 patients in the
cognitive impairment.
placebo group. The results were homogenous across the studies,
Chi-squared statistic = 3.07 (df=3). Using a fixed effects model,
the Peto odds ratio for improvement in the subjects treated with
RESULTS CDP-Choline as opposed to the subjects treated with placebo was
Results are described for the different outcomes comprising at- 8.89 [5.19, 15.22].
tention, memory testing, behavioural rating scales, global clinical In two studies with 30 Alzheimer’s patients and 445 CVD patients,
impression and tolerability to the drug. the CIBIC+ evaluation was used to quantify the clinical changes
Attention after treatment. The resulting effect is very small and from other
analyses there is evidence that the procedure to apply this method
Reaction time results were obtained from six of the studies in- (CIBIC+) of assessment to the clinical appraisal of changes is not
cluded in this review for a total of 760 patients (369 treated with
well suited for CVB patients.
CDP-choline and 391 with placebo). In these studies, all data were
obtained using paper and pencil procedures. The results from these Tolerability
diverse studies are homogeneous, even though they include pa-
Tolerability was assessed in 891 subjects, 452 subjects treated with
tients of different clinical groups and different research procedures
CDP-choline and 439 subjects treated with placebo. Safety data
for the evaluation of attention reactivity and proficiency. Using
were also homogeneous across studies. Using a fixed effects model,
the SMD (standardised mean difference) and FE (Fixed Effect)
the Peto Odds Ratio for no adverse effects of this drug compared
model, the summary effect size is -0.08 [-0.23, 0.06]. This result
with placebo was 1.61[0.98, 2.65], i.e. CDP-Choline tended to
is statistically not significant.
be associated with less adverse effects than placebo.
Memory
Memory assessment has been part of the assessment of subjects
in the majority of the CDP-choline studies. The meta-analysis of DISCUSSION
the memory tests included 441 in the CDP-choline group and This review examines clinical studies of CDP-choline from a long
453 in the placebo group from nine studies, for a total of 894 ago as 1978 and with diverse methodological approaches. Despite
subjects. Memory is complex and different assessment procedures these technical difficulties, it has been possible to identify and
have been used in the studies. Mostly for this reason, all these select a core of 13 double-blind, placebo controlled clinical studies
studies demonstrated a not homogeneous result allowing for the with available numeric data and compliant with the randomization
use of the SMD and the random effect model. The effect size was criteria adopted by the Cochrane group.
0.39 [0.10, 0.68] which is statistically significant.
The included studies were found to be heterogeneous for sub-
Using the five studies which reported memory test results in 645 ject diagnoses, route, dose and duration of treatment with CDP-
participants with cognitive deficits associated with cerebrovascu- choline, and for the outcomes in the domains of memory and be-
lar disorders, the meta-analysis of memory function revealed ho- haviour. At the present time, the evidence for efficacy of this drug
mogeneous results and there was evidence of a positive effect on is based on a majority of participants who were evaluated for 3
memory of 0.21 [0.06, 0.37].
months; none of the included studies evaluated its efficacy beyond
One study performed on 28 Alzheimer’s dementia patients used that period.
the ADAS-cog but the number was too small to give a definite
The more recent studies have adopted a multidimensional ap-
indication of the usefulness of CDP-choline in this type of patients.
proach to assess the effects of CDP-choline, including multiple
Behaviour aspects of behaviour and cognition. Some regulatory authorities
have preferred to evaluate new drugs for people with cognitive im-
Behaviour was measured using four different scales in seven in-
pairment using a single objective outcome approach. This has the
cluded studies analysis of 814 subjects, 397 patients in the CDP-
advantage of not relying upon multiple comparisons but has the
choline group and 417 in the placebo group. There was hetero-
disadvantage of limiting modality of efficacy of the drugs studied.
geneity in the results (Chi squared test = 48.18, df = 6). The effect
size of CDP choline on these behavioural scales was -0.70 [-1.20, The multidimensional approach allows for the analysis of conver-
-0.20] using the random effects model with the standardised mean gence of results of the same treatment obtained in diverse domains
difference. This was evidence of a positive effect of CDP-choline of the clinical picture. This convergence is a very important factor
on behaviour. in evaluating the validity of a treatment in the field of dementia

Cytidinediphosphocholine (CDP choline) for cognitive and behavioural disturbances associated with chronic cerebral disorders in the 3
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and related disorders. There is no single assessment tool which AUTHORS’ CONCLUSIONS
has been demonstrated to be reliably predictive of the important
functions of everyday life (the only valid criteria to a patient, to Implications for practice
his/her carers and to his/her physician).
There is evidence that CDP Choline has a positive effect on mem-
Results of this meta-analysis provide evidence that there is a pos- ory and behaviour in at least the medium term and especially with
itive and consistent effect of CDP-Choline on memory and be- patients suffering of cognitive deficits associated with cerebrovas-
haviour confirmed by a generalized positive clinical impression. cular disorders.
There was no evidence that there were any significant problems
The number of studies dedicated to primary degenerative demen-
in the tolerance for this medication. However, the average max-
tia patients is too small to permit a comparative analysis between
imum length of the studies performed with CVD patients is of
the various traditionally accepted clinical forms of dementia in
3 months. This relatively short length of controlled observation
order to clarify the specific efficacy of CDP-choline in chronic
of these patients when compared with similar studies performed
cerebrovascular disorders and other forms of dementia.
with Alzheimer’s disease patients is mostly due to practical reasons
in conducting clinical controlled studies with this drug for pro-
Implications for research
longed periods of time. The most common administration modal-
ity for CDP-choline is by intramuscular injection, once a day. A Further research with CDP-choline should focus on longer term
cyclic pattern of administration has been developed in order to studies in subjects who have been diagnosed with currently ac-
alternate periods of three weeks with injections to same length cepted standardised criteria, especially vascular dementia.
periods without injections. It is extremely difficult to obtain the
authorization from ethical committees to perform clinical stud-
ies controlled vs. placebo for longer periods of time where sizable
numbers of patients should receive daily injections of inactive flu-
ACKNOWLEDGEMENTS
ids for prolonged periods of time. The most recent study (Senin
2003) was performed in a crossover fashion in order to facilitate Several members of the Cochrane Dementia Group have actively
the approval of the experimental protocol, but it was not possible participated in the preparation of this review. In particular we are
to prolong the length of each arm of the study for more than three indebted to Leon Flicker and Jacqueline Birks who have made a
months. substantial contributions to its final compilation.

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SOURCES OF SUPPORT

External sources of support

• No sources of support supplied

Internal sources of support

• No sources of support supplied

INDEX TERMS

Medical Subject Headings (MeSH)

Aged; Cerebrovascular Disorders [∗ drug therapy]; Chronic Disease; Cognition Disorders [∗ drug therapy]; Cytidine Diphosphate
Choline [∗ therapeutic use]; Dementia [∗ drug therapy; psychology]; Mental Disorders [∗ drug therapy]; Nootropic Agents [∗ therapeutic
use]; Randomized Controlled Trials

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MeSH check words
Human

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