Arch. Gerontol. Geriatr. suppl. 6 (1998) 269-274
0167-4943/98/$!9.00 © 1998 Elsevier Science Ireland Ltd. All right reserved
NOOTROPIC TREATMENT AND COMBINED THERAPY IN AGE-ASSOCIATED MEMORY IMPAIRMENT
L. ISRAEL, M. MYSLINSKI3 and D. KOZAREVlCb
Institute of Psychology, University Lyon II Lumi£re, 5 Av. Pierre Mendes France, F-69676 Bron Cedex, France; aUFR SHS University Grenoble II, B.P. 47, F-38040 Grenoble Cedex 9, France; and DCenter for Multidisciplinary Studies, University of Belgrade, Kneza Viseslava, 1. Y-11000 Belgrade, Yugoslavia
SUMMARY
A double-blind randomized trial was performed involving 162 patients with age-associated memory impairment (AAMI) selected and followed by their general practitioners- Selection was based upon the criteria adopted by the National Institute of Mental Health Work Group and applied to persons over 50 years of age who have experienced the onset of memory loss after early adulthood, but who are neither demented nor depressed. Two intervention methods, a drug and a cognitive therapy in combination, were assessed. The main purpose of the clinical trial was to compare the efficacy of memory training programs (MTP), when combined with a nootropic drug (Piracetam) at two different doses (2.4 and 4.8 g/day) and when given to a group receiving a placebo medication. Therefore, 3 randomized parallel groups, of 54 patients each, were followed for 3 months. After a placebo wash-out period of 10 days, one group began receiving 2.4 g/day of drug treatment, the second group 4.8 g/day and the third a placebo. The 90-minute MTP sessions were conducted once a week at the University Geriatric Center, in Grenoble, France, for groups of 8 to 10 participants. To determine the best therapeutic sequence, we randomly subdivided each main group into two subgroups, one of which started the 6-week MTP immediately and the second began the training 6 weeks later. A total of 135 patients, 45 in each group, completed the study. Combined therapy was most effective in patients whose baseline performance on memory tests was the lowest. The best results were observed with 4.8 g/day, especially when training sessions began after 6 weeks of drug treatment. This result was confirmed by the principal investigator global assessment. Finally, and most importantly, this study shows that the patients with AAMI whom general practitioners routinely encounter in their practices can improve memory performance through combined intervention methods.
Keywords: nootropic treatment, memory training, combined therapy, AAMI INTRODUCTION
Over the last decade, research interest has been focused on the aging process, normal forgetfulness, amnesic syndrome, but also and above all to effective therapies of memory disorders (Israel, 1985). Considering such treatments, one must distinguish between two kinds of intervention. First the pharmacological one, assumed to have an impact on cerebral functions and cognition, second, memory training program (MTP) which in addition, influences both cognitive and affective disorders (Israel, 1988a; Neyroud et al., 1988). Keeping in mind such target points, our team in France has performed several clinical trials, involving more than 500 patients, in which Piracetam treatment was combined
with MTP (Israel, 1989). Besides of combined therapy, the originality of the present study concerns two new aspects. First, this study was conducted in primary care, including the participation of general practitioners (CP) (Israel et al., 1994). Second, the patients selected were characterized by age-associated memory impairment (AAMJ). This is why such a study is probably one of the first concerning patients on the border-line between normality and pathology, selected and followed up by their CP and treated with both nootropic treatment and MTP.
PATIENTS AND METHODS
This double-blind, randomized trial was carried out, involving 162 patients followed over three months. Twenty-seven CP participated to the study; each one selected six patients with AAMI. The aims of the study were: (i) to assess the efficacy of two doses of a Nootropic drug in comparison with placebo and in combination with MTP; (ii) to identify drug responders.
According to our rationale, forgetfulness was the main target variable for assessing efficacy. Many reasons justify our choice. First, experiments on animal models of induced amnesia: many previous studies had already demonstrated the effect of this particular nootropic drug as a protection against hypoxia, amnesia, and other different aggressions on the brain (Giurgea et al., 1971). These effects were measured through enhancement of retention and learning abilities. Secondly comes complaints of the elderly usually concerning forgetfulness in daily living activities. Such forgetfulness appears to be linked to the lability of “mne-sic traces” as well as to difficulties in recall strategies (Israel et al., 1994).
If we admit that forgetfulness could be considered as an acute and temporary amnesia, a treatment which improves resistance to amnesic factors has some chance of decreasing the frequency and/or severity of forgetfulness not only in animals but also in humans, and thus of enhancing global cognitive functioning. Our basic hypothesis was that such a drug could have an action on the underlying structures responsible for the maintenance of the “mnesic trace”, while memory training wouid be more specifically aimed at developing recall strategies. Combined therapy should therefore increase the therapeutic benefit, in the sense of a better well-being in daily life. Thus, it appears necessary to focus on healthy patients, neither demented nor depressed, mainly characterized by reduced memory recall abilities and presenting complaints concerning difficulties in in every day activities.
The diagnostic criteria of AAMI (Crook et al., 1986) proposed by a NIMH workshop describe memory decline with age in comparison with young adults. The term AAMI is applied to people over 50 years of age characterized by the presence of memory-related complaints in daily living, and by the absence of any other pathological condition such as dementia or depression. Such memory disorders have a non-specific etiology, are isolated and sporadic, and have a progressive onset. In our study, severely depressed patients were excluded by means of the geriatric depression scale (CDS) of Yesavage (Brink et al., 1982).
A third reason, related to our population sample, justifies the choice of forgetfulness as the main variable. In fact, if the selection of patients was based on memory disturbances exclusively, it would be very difficult to have an homogeneous population sample, because memory disorders are somehow present in almost all pathological conditions. Besides, as all drug trials demonstrate effects on various aspects of memory functioning, a specific variable such as forgetfulness is more easily and objectively assessed than other memory variables.
Consequently, forgetfulness appeared as the main target variable for measuring outcome and was assessed by three different approaches: (i) patient’s complaints; (ii) cognitive difficulties in activities of daily living, and (iii) performance on psychometric tests. Forgetfulness was objectively measured in terms of retention, assessed by memory recall tests. The performance test battery was measuring five mental activities: memory, attention, perception, orientation and learning. Memory retention was the parameter used to assess efficacy (Israel, 1988b). Severity of complaints were subjectively measured by means of the cognitive difficulties scale (CDS) of Mac Nair and Kahn (1983). Different raters evaluated the patients. A psychologist was responsible for administering two test batteries and a physician for assessing clinical changes and for rating a questionnaire on cognition and general well-being. Finally, the patient himself had to complete two self-assessment questionnaires reflecting cognitive difficulties in daily living as well as complaints. The 3 raters also gave a global assessment.
The study included 3 parallel groups of 54 patients aged 55 years and over, who were followed over 3 months. After a placebo wash-out period of 10 days, one group received 2.4 g/day of the drug, the second group 4.8 g/day and the third one a placebo. The drugs were prescribed daily for three months. Each group was then subdivided in two by randomization: one subgroup began MTP for the first six weeks the second one started MTP after six weeks of drug treatment. This meant that for the 2.4 g/day group, 27 patients, out of 54, had MTP during the first period in addition to drug treatment, while the 27 other patients started MTP in the second half of drug therapy, i.e., after 45 days of drug treatment. The same applies to the other groups.
The mean age of patients was 68.5 years; 16 % were males and 84 % females; a low educational level appeared in 39.5 % of the cases and a high one in 60.5 %. The three groups were comparable as to age, sex, and educational level. Baseline measurements on performance tests and rating scales were also comparable. During the first six weeks, 10 patients dropped out of the study, and another 17 patients left during the next six weeks. Thus, over the period of 3 months, there was a total of 27 drop-outs, representing 16 % of the sample, with exactly 9 drop-outs from each group. Considering the 10 drop-outs of the first 6 weeks, we noticed that 8 among them were high placebo responders.
RESULTS AND DISCUSSION
if we first consider the global assessment made by the principal investigator, striking differences were found between the 3 groups. Very good results were obtained in 42.5 % of subjects who received the higher dose of drug (4.8 g/day); 11 % of subjects in the lower dose (2.4 g/day), while only 2 % appears in the placebo group. Wild effects were observed in 56 % of placebo subjects, 16 % on lower dose and 6.5 % on higher dose. The Chi-square test showed that those differences were statistically significant.
Concerning assessment of forgetfulness measured through memory recall, an improvement of 28.5 % appeared from baseline for the high dose group, 18.4 % for the low dose group, while for placebo it was only 11 %. These differences were statistically significant. When comparing subgroups with MTP during the first and second period, the greatest improvement was observed in the subgroup that received the high dose of drug and MTP during the second period (35.5 %). Comparing all 6 subgroups, the difference was statistically significant.
In consequence, it can be stated that drug treatment at a dosage of 4.8 g/day, and especially when combined with MTP, had a positive effect after a 6-week-treatment on the memory recall abilities of the more impaired patients with AAMI.
Finally, side effects were more frequent with placebo than with drug (7 versus 2).
Importance of signs and symptoms
To distinguish placebo responders from non-responders, we based our judgement on changes occurring in 22 signs and symptoms during the 10-day wash-out period. When a present sign disappeared or an absent sign appeared this was considered a change. The number of signs which changed was then classified into one of three categories: 0-2 (non-responders); 3-6 (low responders); and 7-21 (high responders). On this basis, 46 % were placebo non-responders, and 56 % placebo responders, among whom 20 % were high responders and 34 % low responders. The most frequent somatic changes, occurring in almost 30 % of the cases, were pain cramps, dyspepsia, headache and dizziness, while the psychological signs included emotional state, anxiety, sleep disorders, asthenia and tension.
Identification of drug responders
According to the basic hypothesis in our study, forgetfulness was chosen as the main target variable to assess forgetfulness and to identify drug responders. We considered that a difference equal to, or greater than one standard deviation in this variable corresponds to relevant clinical significance. In consequence, we identified the number of patients who improved their performance above this threshold value. On this basis, 53.5 % of patients improved in the higher dose group, 38 % in the lower dose group and only 22 % in the placebo group. These differences were statistically significant. But a very interesting trend in our findings was that among the drug responders, there was a much higher percentage of subjects with very low baseline results on performance tests before treatment. This means that the more deteriorated subjects derived more benefit from the treatment.
Regardless the specific results concerning this drug, this study contributed to some other interesting findings. First, it showed a tremendous importance of placebo effects on this population sample. This fact might constitute a bias when follow up measurements, especially in open studies, are mainly based on subjective self-assessment. Therefore, in priority it should be useful to identify responders through follow up studies, as well as to determine the value of improvement corresponding to clinically relevant changes. Comparing with other existing methods of regrouping signs and symptoms (Finkel et al., 1996), we have chosen the number of changes of signs in order to differentiate non responders group from low and high responders. Such an approach may have important implications for the diagnosis and treatment interventions (Finkel, 1996). Second, we have demonstrated that such subjective assessment was not correlated with objective measures of memory performance; therefore in such studies objective parameters are absolutely necessary. Third, psychometric results of the study have also showed some kind of shifting among cognitive functions, in particular, memory recall capacities appeared independent from learning as well as from other cognitive abilities involving reasoning, encoding, information processing (Israel et al., 1994). Finally, these findings may suggest that this AAMI population is mainly characterized by forgetfulness occurring independently from a baseline global cognitive performance functioning.
In conclusion, it should be stressed that elderly patients with forgetfulness can effectively be treated by combining drug treatment and memory training. If we admit that mental autonomy may be preserved through combined therapy, then this study constitute a good example and model of the more adequate and possible intervention methods. In particular, it illustrated how treatment of cognitive and affective disorders through such a combination of therapies, drug for
cognitive, and training for affectivity, may enhance the patient benefit in their daily life.
REFERENCES
Brink, T.L., Yesavage, J.A., Lum, O., Heersema, P.H., Adey, M.and Rose, T.L. (1982): Screening tests for geriatric depression. CJin. Gerontologist, 1, 37-43.
Crook, Th., Bartus, R.-T., Ferris, S.-H., Whitehouse, P., Cohen, G.-D. and Gershon, S. (1986): Age-associated-memory-impairment: Proposed diag
nostic criteria and measures of clinical change. Report of a National Institute of Mental Health Work Group, Dev., Neuropsychol., 2, 261-276.
Giurgea, C., Lefevre, D., Lescrenier, C. and David-Remacle, M. (1971): Pharmacological protection against hypoxia-induced amnesia in rats. Psy-chopharmacol., Berlin, 20, 160-168.
Finkel, S. (1996): New focus on behavioral and psychological signs and
symptoms of dementia. Internat. Psychogeriatr., 8 (Suppl. 3), 215-216.
Finkel, S., Costa e Silva, J., Cohen, G., Miller, S. and Sartorius, N. (1996): Behavioral and psychological signs and symptoms of dementia: A consensus statement on current knowledge and implications for research and treatment. Internat, Psychogeriatr., 8 (Suppl. 3), 497-500.
Israel, L. (1985): Memory and mental stimulation: Assessment in clinical trials. In: C.-J, Brainerd and V.-F Reyna (eds.): Developmental Psychology, pp. 9-17. Elsevier Science Publishers B.V., Amsterdam.
Israel, L. (1988a): Entrainer sa m£moire. Guide 3 I’intention des moniteurs. Editions du Centre de Psychologie Appliqu6e, Paris (in French).
Israel, L. (1988b): Batterie de fluidite pour les personnes agees. Editions du Centre de Psychologie Appliquee, Paris (in French).
Israel, L. (1989): Memory training program as a reference to the clinical evaluation of drugs in memory disorders. Arch. Gerontol. Geriatr., Suppl. 1, 223-230.
Israel, L., M6lac, M., Milinkevich, D. and Dubos, G. (1994): Drug therapy and memory training programs: A double-blind randomized trial of general practice patients with age-associated-memory-impairment. Internat. Psychogeriatr., 6, 155-170.
Mac Nair, D.-M. and Kahn, R.-J. (1983): Self-assessment of cognitive deficits. In: Th. Crook, S. Ferris and R. Bartus (eds.): Assessment in Geriatric Psychopharmacology, pp. 137-143. Mark Powley Associates Inc., New Canaan.
Neyroud, J., Israel, L., Raymond, I., Simeone, I. and Jeanneret, O. (1988): Randomized trial on memory training in the over 60s. The Lancet, 23, 932.
