Download Long-term and high-dose piracetam treatment of Alzheimer`s

Long-term and high-dose
piracetam treatment of
Alzheimer's disease
B. Croisile, MD; M. Trillet, MD; J. Fondarai, PhD; B. Laurent, MD; F. Mauguiere, MD, PhD;
and M. Billardon, MD
Article abstract—Preclinical research suggests that piracetam (a nootropic drug) may improve cognitive functions,
but previous studies have failed to demonstrate a clear benefit for the treatment of Alzheimer's disease (AD). We
report a 1-year, double-blind, placebo-controlled, parallel-group study with a high dose of piracetam (8 g/d per os) in 33
ambulant patients with early probable AD. Thirty subjects completed the 1-year study. No improvement occurred in
either group, but our results support the hypothesis that long-term administration of high doses of piracetam might
slow the progression of cognitive deterioration in patients with AD. The most significant differences concerned the
recall of pictures series and recent incident and remote memory. The drug was well-tolerated.
NEUROLOGY 1993;43:301-305
Piracetam (2-oxo-l-pyrrolidineacetamide), a compound in the nootropic class of psychotropic drugs,
has been proposed to enhance learning and memory. The neurochemical mechanism of action of
piracetam is not understood. Although nootropic
drugs have no affinity for cholinergic receptors and
are not cholinesterase inhibitors, they stimulate
cerebral acetylcholine synthesis and release. 1
Deficits in brain cholinergic neurons play an important role in the physiopathology of Alzheimer's disease (AD),2 and any neurochemical improvement in
the central cholinergic mechanisms should be of
major interest in the treatment of the memory and
cognitive disorders of AD. In animal experiments,
an inverted U-shaped dose-response curve
occurred, and piracetam demonstrated an enhancement of learning and a positive influence on disturbed learning and memory processes. 3 '5
Piracetam is reported to protect rabbits and
rodents from hypoxic-induced amnesia6 and electroconvulsive shock-induced amnesia, 7 and to
reverse scopolamine-induced amnesia in mice. 8
Some clinical studies with piracetam on elderly or
demented patients showed an improvement of performance on memory and behavioral tests.9'10 In
other trials, piracetam did not dramatically
improve performance in AD, although significant
differences could be observed in some of the tests.11
Most often, piracetam has been tested with low
doses (2.4 to 4.8 g/d) or for short periods (between 1
and 4 months). It is significant that in all studies
no side effects were observed after piracetam
administration.
Our objective was to determine whether longterm oral administration of a high dose of piracetam (8 g/d) could improve the symptoms of
patients with AD. The study was a randomized
double-blind, placebo-controlled, parallel-group
trial, with a 1-year follow-up.
Methods. Subjects. Thirty-three ambulant patients (14
men, 19 women), aged 57 to 81 years (mean, 66.4 years;
SD = 8.2), consented to participate in the study, but only
30 completed the study (12 men, 18 women; aged 57 to
81 years; mean, 66.1 years; SD = 7.8). All patients had a
history of a slowly progressive memory impairment and
met the clinical diagnosis of probable AD according to
NINCDS-ADRDA criteria. 12 A Mini-Mental State
Examination (MMSE)13 score of between 15 and 20 was
considered moderate dementia. Patients or, if they were
not judged competent, their legal guardians were asked
to give written informed consent and had been described
the purpose and procedure of the study. Other possible
causes of dementia were ruled out. There was no incidence of depression, and the patients had no history of
stroke, traumatic head injury, or alcohol abuse. They had
no localizing neurologic signs. All Hachinski Ischemic
From Hopital Neurologique (Dr. Croisile, and Prof's. Trillet and Mauguière), Lyon; the Institut Laval, Hôpital Sainte Marguerite (Prof. Fondarai),
Marseille; Hôpital Bellevue (Prof. Laurent), Saint Etienne; and Medical Department, UCB Pharma (Dr. Billardon), Nanterre, Fra nce.
Supported by a grant from UCB-Pharma, Nanterre, France.
1 <;,sented in part at the 43rd annual meeting of the American Academy of Neurology, Boston, MA, April 1991.
Received December 13, 1991. Accepted for publication in (inal form June 23, 1992.
Address correspondence and reprint requests to Dr. B. Croisile, Department of Neurology, Hopital Neurologique, 59 boulevard Pinel, 69003, Lyon,
France.
February 1993 NEUROLOGY 43 301
Table 1. Results of the piracetam group at MO
(baseline) and M12 for the 14 tests
Table 2. Results of the placebo group at MO
(baseline) and M12 for the 14 tests
Scale scores14 were less than 4. Laboratory biochemical
screening tests were normal (serum vitamin B12, folate
and calcium levels, and thyroid function tests). Serology
for syphilis was negative. EEGs were normal in 14
patients and showed otherwise nonspecific slow waves.
Brain CTs showed only cerebral cortical atrophy with mild
ventricular enlargement. All patients were free of any centrally active or psychotropic medications for at least 4
weeks before inclusion in and throughout the study.
Drug procedure. This was a 1-year, double-blind study
with a high dose of piracetam (8 g/d per os) versus placebo. The study design was conducted in two parallel
groups and included no crossover and no initial dose-finding phase. Crossover studies are less appropriate for the
investigation of long-term effects.15 Before treatment,
there was no significant difference between the piracetam
and placebo groups on any demographic variables. The 14
patients who completed the study in the piracetam group
were six men and eight women aged 64.8 years (SD = 7.6;
range, 57 to 79 years), with a mean educational level of
8.9 years (SD = 4.4). The 16 patients who completed the
study in the placebo group were six men and 10 women,
aged 67.3 years (SD = 8.1; range, 57 to 81 years), with a
mean educational level of 8.9 years (SD = 3.9). The mean
disease duration was 3.6 years (SD = 2.1) for patients in
the piracetam group and 3.4 years (SD = 2.1) in the placebo group. Hachinski Scale was 2.1 ± 0.8 in the piracetam
group and 1.8 ± 0.9 in the placebo group.
Evaluation. The outpatients were followed regularly,
and the evaluations were performed by the same physician for the same patient. Every 3 months, from MO
(month 0) to M12, the following were carried out: clinical
examination, assessment of tolerance to the drug, evaluation of observance of the treatment, and estimation by
the family of the drug's effectiveness in daily living.
Neuropsychological tests were performed at MO, M6, and
M12. Subjects' performances were assessed by means of
a battery of 14 neuropsychological tests, which took 45
minutes to perform. The MMSE was used as a test of
global evaluation of the mental condition. The mood
state was evaluated by the 10 subscales of the
Montgomery and Asberg Depression Rating Scale
MADRS16; behavior and activities of daily living were
assessed through relatives with the Blessed A. 17
Language was assessed by the Aphasia Battery.l8 It con-
sists of seven subtests derived from the Bostona
Diagnostic Aphasia Evaluation: expressive language
oral naming, image discrimination, body part identificaj
tion, reading comprehension, auditory comprehension^
and written naming. A score of 0 indicates normal
guage; a score of 35 means total aphasia. Memory
evaluated with several tests, chosen to investigate
ent forms of memory: verbal, visual, recent incidentj
effortful, episodic, semantic, short term, and long term!
Parallel forms were always used at MO, M6, and M121
The Visuo-Verbal Learning Test19 was administered inl
three steps: naming of 10 black and white line drawings!
(Rey 1), recognition of the same faded images (Rey 2)J
and immediate free recall of the 10 names (Rey 3). Three]
Digit Span subtests Were used: Digit Span Forward^
Digit Span Backward, and a Logical Digit Span (5-10-15,1
etc.). For each span, the score was the sum of the suc-j
cessful digits series. Remote semantic memory was eval-J
uated with two series of semantic (general) questions: aj
list of six historical and geographical questions (names of|
capital cities, rivers, or mountains; famous historical!
dates) and recognition of six famous color photographs!
(French presidents, famous actors, cars, and monu~f
ments). We tried to test the recent incident memory: anl
ordinary sentence was spoken by the physician during!
the examination, and 5 minutes later, the patient was|
asked to recall the sentence (2 = total correct recall, 1 =|
partial recall, and 0 = no recall). Lastly, two tests werej
used to assess logical memory, with a verbal test (imme-1
diate recall of a short story with 22 memory units) and a|
visual test (complex figure test: free recall, after initial!
copy, of a complex figure with 12 units).20
|
302 NEUROLOGY 43 February 1993
1
Results. Three patients (two treated with pira-J
cetam and one with placebo) dropped out of the trial|
for personal reasons. The remaining 30 patients!
were included in the statistical analyses. Resultsl
are expressed as means in tables 1 and 2. MMSS
was measured only at MO and M12 to avoid learnl
ing effects: at M12, nine of 14 piracetam patients!
and 10 of 16 placebo-treated patients had deterio|
rated by comparison with MO. Repeated single-facl
tor ANOVA for MMSE identified no significant difJ
ference between the two groups on performance a|
Table 3. Fisher's discriminant analysis: Percentage
of relative contribution of each test for the
difference between piracetam group and placebo
group at M12
either MO or M12. The results of the 13 other subtests did not differ significantly between the two
groups at MO (repeated ANOVA). Patients in both
groups deteriorated between MO and M12—the
piracetam group in 11 of 14 tests and the placebo
group in 12 of 14 tests. However, repeated singlefactor ANOVA only identified a significant difference at M12 for subtest Rey 3 (F = 7.24; p < 0.01).
Other statistical methods can be used to assess
the differences between the piracetam and placebo
groups. We determined in which cases the difference between the regression slopes for the variables as a function of time were greater than double the standard deviation. There was a significant
difference for four subtests: Aphasia Battery (p <
0.01), Logical Story (p < 0.01), Key 2 (p < 0.05), and
Recent Memory (p < 0.05). The linear model was
not applicable to Key 3, but ANOVA demonstrated
that piracetam-treated patients performed better
on this subtest.
We tried to find the most general and the most
specific statistical approach because the number of
patients in the study was small, the results varied
widely between patients, and the AD was clinically
heterogeneous. Furthermore, were only variance
malyses to be used, the variations we wanted to
identify might have been swamped by random variations. Fisher's discriminant analysis 21 takes all
the variables into account simultaneously and measures their relative contributions. The contribution
of some of the individual variables is large: Rey 3
(32.3%), Recent Memory (22.0%), and Remote
Memory (15.8%) favor a slowing of the deterioration in the piracetam group (table 3).
Consequently, these three subtests make up 70.1%
of the total contribution. By contrast, only two variables favor the placebo: Rey 1 and Digit Span
Backward, with a combined relative contribution of
0.6%. Fisher's discriminant analysis can also be
used for internal verification, by determining to
which of the two groups (piracetam or placebo) a
given patient belongs. Every patient was tested
and the results are excellent for the piracetam
group: 13 of 14 were correctly placed (93%). Eleven
of the 16 placebo-treated patients were correctly
placed, such that 24 of the 30 patients (80%) were
correctly classified by the test.
Fisher's discriminant analysis avoids the generation of pseudo—p-values, since all the variables are
included, giving a single combination of variables.
Stepwise discriminant analysis, however, risks
generating pseudo-p-values. Nevertheless, this
analysis was performed (BioMedical Data
Processing statistical software, Los Angeles CA),
and the-results confirmed those of Fisher's discriminant analysis. The three most discriminant factors
were Rey 3 (F = 5.84, with 1 and 28 degrees of freedom), Rey 3 + Remote Memory (F = 4.95, with 2
and 27 degrees of freedom), and Rey 3 + Remote
Memory + Recent Memory (F = 5.08, with 3 and 26
degrees of freedom).
The correlations between the subtests were
determined, to assess the degree of association
between the 13 subtests (MMSE not included)
taken into account in Fisher's discriminant analysis. Only eight of the 78 possible correlations were
significantly different from 0: MADRS and Aphasia
Battery; Blessed A and Remote Memory; Aphasia
Battery, Blessed A, and complex figure; Remote
Memory, Blessed A, and Logical Digit Span; and
Rey 3 and Rey 2. Overall, 90% of the possible correlations were not significantly different from 0, and
of the eight possible correlations significantly different from 0, only three scored more than 0.6, two
more than 0.4, and three more than 0.3. Thus, the
subtests overall approximate to being independent.
We therefore compared the number of improved
and unchanged scores for the 13 subtests in the
piracetam group (98/182) with the placebo group
(87/208). The difference between these two results
is significant (chi-square = 5.62,p < 0.02).
Few side effects occurred during the course of
the study—one case of constipation in the piracetam group and one case of gastric pains in the
placebo group. Piracetam had no effect on vital
signs, and routine tests of renal, hepatic, and
hematologic functions remained normal. No significant changes in weight, heart rate, or blood pressure occurred in either group.
Discussion. Our study showed a significant slowing of the deterioration in patients with AD after
high-dose and long-term treatment of piracetam.
Although repeated-measures, single-factor ANOVA
only identified a significant difference at M12 for
subtest Rey 3 (recall of the names of the figures),
the difference between the regression slopes of
piracetam and placebo groups was significant for
four subtests: Aphasia Battery, Logical Story, Rey
2, and Recent Memory. Furthermore, Fisher's discriminant analysis, which is a more global analyFebruary 1993 NEUROLOGY 43 303
sis, demonstrated a large contribution (70.1%) of
three subtests to the difference between the two
groups: Rey 3, Recent Incident Memory, and
Remote Memory. A stepwise discriminant analysis
confirmed that these three subtests are also the
most discriminant factors.
Therefore, after a 1-year study, some subtests of
the patients with piracetam were significantly different from the placebo group, thus demonstrating
a partial slowing of the deterioration. It appears
that piracetam has its main effect on memory performance, and semantic and implicit memory seem
better preserved than effortful declarative and
episodic memory. This latter fact might be in accordance with the slight, although nonsignificant,
improvement of the attentional abilities (Digit
Span Backward). There is a relationship between
attention and the cholinergic system: explicit memory and implicit memory are both decreased when
attention is reduced by anticholinergic drugs such
as scopolamine. 22 Conversely, the anticholinesterase physostigmine improves attentionbased tasks such as the Digit Symbol and
Cancellation tasks.23 Due to its cholinergic-enhancing effect,5 it is conceivable that piracetam might
improve attention and memory, as observed with
cholinomimetics.
Results obtained in other studies with piracetam, alone or in association with lecithin, are not
convincing because of the brevity of the trial period, the low dose used, or the small number of
patients included in the studies.11-24 The brief time
that subjects were studied might have made it difficult to distinguish treatment effects from the natural course of the disease. High doses of piracetam
are needed to have a therapeutic effect in
myoclonus,25'26 which suggests the interest and
need of high doses of piracetam when tested in AD.
Some piracetam trials have demonstrated mild
clinical benefit in AD on some attentional tests
(immediate recall, attentional focusing)11 or memory
tests (Buschke Selective Reminding Task).10'24
Additionally, over a 2-week period, the cerebral
glucose metabolism was significantly improved by
piracetam in a positron emission tomographic
(PET) study without cognitive testing.27 The effectiveness of other nootropic drugs is also difficult to
determine in AD; some improvement on certain
neuropsychological tests was shown with oxiracetam,28 aniracetam,29 or pramiracetam.30 However,
there was no significant difference between drug
and placebo groups regarding the clinical degree of
disability. Moreover, pramiracetam studied in two
patients with AD afforded no enhancement of
regional glucose metabolism in a PET study/50
Successful AD treatment could improve cognitive and memory tasks or daily living activities.
However, it has been suggested that long-term
lecithin treatment might alter the rate of progression of AD rather than yielding a real improvement.^1 Other studies have also demonstrated that
cholinergic precursors might have prophylactic
304 NEUROLOGY 43 February 1993
effects on the cognitive symptoms -of AD. 32,33
Slowing of deterioration is more difficult to analyze
than improved performance on a test. Although not
dramatic, slowing is a worthwhile benefit, as we
found with piracetam, even without clear improvement of cognitive or behavioral symptoms, Our
results suggest that a high dosage and long administration period is necessary for cognitive benefits
to occur with piracetam. This effect on memory and
attentional performance could confirm that piracetam enhances cholinergic neurotransmission.
The lack of dramatic benefit can be explained by
the many neurobiochemical and neuropathologic
factors involved in AD progression. Therefore, it is
probably necessary to correct more than one neurotransmitter deficit in AD to reverse the course of
the disease. Although piracetam did not produce a
spectacular improvement in our trial, it may provide prophylactic benefits, and it remains a candidate for AD therapy, alone or in combination with
other drugs.
I
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