Inkblot: The Undergraduate Journal of Psychology • Vol. 2 • September 2013 | 43 Treatment of Alzheimer’s Disease: A Comparison of The purpose of this paper is to examine whether oxiracetam and aniracetam are more effective than donepezil and tacrine, two drugs currently used to treat Alzheimer’s disease. Past research suggests that oxiracetam and aniracetam are more therapeutical y efficacious than donepezil and tacrine in the treatment of Alzheimer’s dis- ease symptoms (i.e., cognitive deterioration, tolerability, and quality of life). Oxiracetam and aniracetam appear to reverse the cognitive deficits of Alzheimer’s disease, whereas donepezil and tacrine seem to only slow down the deterioration of cognitive abilities. Research also suggests that oxiracetam and aniracetam may cause improve- ments in quality of life, whereas donepezil and tacrine provide mild, if any, improvement in quality of life. Future research on Alzheimer’s treatment should be conducted on large populations and focus on direct comparisons of the efficacy between Racetam and non-Racetam compounds.
This literature review will discuss the effects of anirace- n.d.). The use of aniracetam and oxiracetam in treating tam and oxiracetam on patients afflicted with Alzheim- Alzheimer’s disease was researched heavily in the 1990s er’s disease. Alzheimer’s disease is an irreversible and (Bottini, Val ar, Cappa, Monza, Scarpini, Baron, & Scar- progressive disease. Symptoms of the disease include lato, 1992; Dager, Loebel, Claypool, Case, Budech, & deterioration in memory, dysfunctional daily living, Dunner, 1992; Davis, Thal, Gamzu, Davis, Woolson, changes in mood and personality, confusion, impaired Gracon, & Doody, 1992; Gouliaev, & Senning, 1994). communication, and loss of bowel and bladder control These studies have shown that the Racetam compounds (National Institutes of Health (NIH), n.d.).
decrease symptoms of Alzheimer’s disease. However, Alzheimer’s disease is caused by a combination the research and clinical use of oxiracetam and ani- of genetic and environmental factors (Gatz, 2006). Typ- racetam has come to a standstill for unknown reasons ical onset of Alzheimer’s disease is above the age of 60 (Kenda & Matagne, 2012). years. A definite diagnosis of Alzheimer’s disease can- Past studies have looked into how these drugs not be determined until an autopsy is performed. Due interact with the brain. Oxiracetam and aniracetam to the need for an autopsy to be performed, individu- work in similar ways: oxiracetam stimulates acetylcho- als may be diagnosed with possible Alzheimer’s disease line utilization in the hippocampus and indirectly stim- through questionnaires, memory diagnostics, blood ulates AMPA glutamate receptors (Gouliaev and Sen- tests, urinalyses, and brain imaging. (NIH, n.d.). ning, 1994). Aniracetam, on the other hand, enhances Current approaches to treating Alzheimer’s dis- the efficacy of AMPA-induced calcium influx, increases ease focus on drug therapy (NIH, n.d.). The purpose of acetylcholine content in the hippocampus and cerebral using drugs is to slow down or delay the onset of symp- cortex, and decreases the dopamine level in the stria- toms in those afflicted with Alzheimer’s disease (NIH, tum and the hypothalamus. An important characteris- 44 | Inkblot: The Undergraduate Journal of Psychology • Vol. 2 • September 2013 tic of these Racetam compounds relates to their effect ness of Bottini et al.’s (1992) study was its small sample on acetylcholine in the hippocampus. Acetylcholine size of 65 participants. Nonetheless, a study by Maina, in the hippocampus has been associated with learning Fiori, Torta, Fagiani, Ravizza, Bonavita, and Macciolli activation and memory; animal models with induced (2008), found similar results using a larger sample size memory impairments have found behavioral deficits in of 289 participants. In particular, the oxiracetam group learning, as well as a decrease in hippocampal acetyl- showed significant improvement on the Blessed De- mentia Scale (BDS); the BDS contains scales that mea- Currently, relatively newer and more popular sure information, memory, and concentration abilities, medications, such as donepezil and tacrine, have been all of which are indicators of cognitive improvement. discovered and are now first-line treatments for Al- In a study by Vil ardita, Grioli, Lomeo and Cattaneo’s zheimer’s disease. Whether these new medications are (1992), similar results in cognitive improvement were more effective than Racetam compounds is an issue that found, where cognitive ability was operationalized as must be addressed. This literature review will explore memory retention, and was tested using word recall and Racetam research that is focused on certain aspects of word recognition. the disease (cognitive ability, and quality of life), includ- Other studies, however, have brought the effica- ing a comparison between Racetam containing drugs cy of oxiracetam on cognitive ability into question. For and recent medications, in terms of their therapeutic example, a study by Green, Goldstein, Auchus, Presley, Clark, Van Tuyl, and Karp (1992) found no therapeu- tic efficacy of the oxiracetam treatment on Alzheimer’s disease. This study, however, had a number of flaws: a small sample size of 24 participants; withdrawal of par- ticipant results; plausible bias (funded by GSK pharma- Oxiracetam, like other Racetam compounds, is ceuticals); and premature termination after one month, not currently prescribed as a treatment for Alzheimer’s instead of the planned three months. Despite its short- disease. However, studies suggest that oxiracetam has comings, the study concluded that oxiracetam did not the ability to slow down, or completely halt, the dis- offer meaningful clinical improvement in cognitive ease’s progression. There are a number of studies that functioning. It is important to note that studies where have shown an improvement in patients’ symptoms researchers found significant positive results were per- pertaining to cognitive ability. In a double-blind, be- formed over a minimum period of 12 weeks (Bottini tween-patient study conducted by Bottini et al. (1992), et al. 1992; Maina, et al., 1989; Vil ardita et al., 1992). the administration of 1600 mg/day of oxiracetam was Thus, the research suggests that oxiracetam requires at observed to significantly improve phonemic memory, least 12 weeks to demonstrate observable positive ef- semantic memory, short-term memory recal , and rec- fects on participants afflicted with Alzheimer’s disease. ognition in Alzheimer’s disease patients. In contrast, a After a thorough review of the oxiracetam literature, steady deterioration in cognitive ability, according to only one methodological y imperfect study was found results found from the same group of neuropsychologi- (see Green et al., 1992). Evidence found in the major- cal tests, was observed in the placebo condition. Most ity of articles suggests that oxiracetam may be effective noteworthy were the results of the semantic memory in improving the cognitive functioning of participants tests (including short story recal , semantic tasks, digit with Alzheimer’s disease (Bottini, et al., 1992; Dager, et span tests, and word list tests), which showed significant al., 1992; Maina, et al., 1989). improvements in the oxiracetam group. A major weak- Quality of life was another factor that was seen Inkblot: The Undergraduate Journal of Psychology • Vol. 2 • September 2013 | 45 to be improved by the use of oxiracetam. Vil ardita, et ability concerns (Bottini, et al., 1992; Dager, et al., 1992; al., (1992) found improved quality of life (as measured Maina, et al., 1989; Vil ardita, Grioli, Lomeo, Cattane, by the non-self-report Luria Alternating Series and In- & Parini, 2008). As discussed, however, the available strumental Activities of Daily Living) in a portion of research is limited. Additional y, since the elderly are their participants medicated with oxiracetam, though often prescribed medication unrelated to Alzheimer’s these improvements were not entirely consistent after disease, further research needs to be conducted involv- 12 months of usage. Bottini et al. (1992) also found im- ing drug interactions.
proved quality of life in the oxiracetam group, as mea- sured by the Italian Quality of Life Scale (IQLS), over Aniracetam the course of 12 weeks, when compared to a placebo There have been a small number of studies group. A study by Maina et al. (1989) made similar con- conducted on the use of aniracetam in the treatment clusions based on the Psychic and Somatic Complaints of Alzheimer’s disease. One such study was a double- in the Elderly (IPSC-E) questionnaire. A case study by blind placebo study conducted by Senin, Abate, Fies- Dager et al. (1992) found that, at an individual level, pa- chi & Gori (1991). In this particular study, researchers tients who were treated with oxiracetam were reported looked at the Rey-15 word test as a measure of memory as being more sociable, performing better in functions feigning, the Corsi test as an assessment of visuo-spatial of daily living, and having a higher positive affect and short term working memory, and the Raven colored level of independent functioning. Upon patients’ dis- progressive matrices as a measure of abstract reason- continuation of the medication, a progressive decline in ing. Some other factors examined in this same study social function and self-care occurred. This selection of were executive attention, as measured by the Gibson literature suggests that oxiracetam improves the quality spiral maze, and selective attention, as measured by of life of patients with Alzheimer’s disease. It is possible the Toulouse-Pieron test. Scores on these psychomet- that an improvement in cognitive functioning might ric tests of cognitive ability all showed an improvement coincide with an improvement in mood and daily liv- in the aniracetam-treated group, whereas the results ing; it is difficult to separate quality of life and cognitive showed cognitive deterioration (a common symptom of Alzheimer’s disease) in the placebo group. The rea- Moreover, the studies conducted by Vil ardita et son for this deterioration is likely due to the fact that al. (1992), Bottini et al. (1992), and Maina et al. (1989) patients in the placebo group were not given Alzheim- have all found high treatment compliance and physi- er’s medication and the disease symptoms progressed. ological tolerability in participants administered with This study is important because it was conducted with oxiracetam. Unfortunately, recent studies on this sub- a large study sample of 109 patients over a long period ject, as noted earlier, have not been conducted. Within of time (~6 months). A large study sample is crucial in the available literature, it was found that this medica- order to observe whether the drug’s effect on a patient tion does exhibit common adverse side effects; the group truly made a difference; a small sample size will gastrointestinal complaints documented include both not be able representative of the effects on a large group nausea and diarrhea (Vil ardita et al., 1992; Bottini et such as a community or province. Ensuring drug trials al., 1992). These side effects occurred in 7%-10% of monitor patients over a long period of time is crucial. oxiracetam-treated participants across studies, as well In this way, researchers can observe the true effects of as in placebo-treated participants; thus these effects the drug on a patient group as time goes on, not just were not oxiracetam specific. The research on oxirace- the acute effects of a medication that may not last. The tam suggests that this drug holds few safety and toler- most resonating result in this study was the improve- 46 | Inkblot: The Undergraduate Journal of Psychology • Vol. 2 • September 2013 ment of test scores pertaining to short-term memory relative to the placebo group (Johannsen et al., 2006). recal , attention ability, and general intelligence/reason- Although this study demonstrated donepezil’s ability to ing to above pre-treatment levels in aniracetam-treated slow down the deterioration of cognitive ability, it failed patients. Since Alzheimer’s disease causes deterioration to demonstrate its ability to halt or improve the cogni- in cognitive abilities (NIH, n.d.), these results suggest tive ability of individuals afflicted with Alzheimer’s dis- the possibility of aniracetam reversing the cognitive ef- ease beyond baseline. Interestingly, patients’ physicians fects of this disease. Further research on this drug may acknowledged an improvement in their patients’ behav- be able to provide additional evidence in support of this iour and cognitive functioning. However, this acknowl- hypothesis. Similar to the other Racetam compounds, edgement of improvement was also noticed when pa- the most common adverse side effects in the adminis- tients’ cognitive scores were declining (Johannsen et al., tration of aniracetam were gastrointestinal symptoms 2006). Consequently, the physicians’ acknowledgement (diaherra, nausea, etc.). However, these symptoms were might indicate a lack of scale accuracy or a bias on their only observed in 7% of the aniracetam patients (Senin part, perhaps due to their prior knowledge of donepe- et al., 1991). These studies suggest that, overal , anirace- zil’s proposed effects. In Johannsen et al.’s (2006) study, tam is well tolerated, and relatively safe for use in pa- the authors found donepezil to be well tolerated. There tients (Senin et al., 1991; Gouliaev & Senning, 1994).
was a low frequency of adverse side effects, though no statistical test was conducted to support this data. The majority of these side effects were mild to moderate and affected the digestive or nervous systems. In general, donepezil does not appear to pose a safety or tolerabil- Donepezil (Aricept) is a common medication ity risk to patients.
prescribed to Alzheimer’s disease patients. Although its therapeutic advantages have been observed in the treat- Tacrine ment of Alzheimer’s disease, not all patients respond to In a double-blind, placebo-controlled study by donepezil. In one study, donepezil was found to be effec- Davis et al. (1992), it was found that treatment with ta- tive in increasing Mini-Mental State Examination scores crine in Alzheimer’s disease patients resulted in a sig- (a test of cognitive impairment used to screen for de- nificant decrease in the decline of cognitive function, as mentia) on 69% of patients, while the remaining 31% of measured by the ADAS. Davis et al. (1992) reported no patients showed uncertain improvements (Johannsen, tolerability or safety issues. Similar to donepezil, tacrine Salmon, Hampel, Xu, Richardson, Qvitzau, & Schindler, did not halt or improve the condition of the disease; 2006). In this double-blind, placebo-controlled study, rather, it appeared to slow down the inevitable deterio- the authors found that at 12 weeks of treatment with ration of cognitive functioning that is symptomatic in donepezil, there were no significant differences in cog- Alzheimer’s disease.
nitive test scores between the placebo and donepezil Using the Instrumental Activities of Daily Liv- group, as indicated by the Mini-Mental State Examina- ing scale (IADL), Knopman, Schneider, Davis, Talwalk- tion (Johannsen, et al., 2006). However, after more than er, Smith, Hoover, and Gracon (1996) found that tacrine 12 weeks of treatment with donepezil, improvements treatment improved daily living in patients treated with in patients’ cognition were observed when measured tacrine compared to the placebo group. However, this by the Alzheimer’s Disease Assessment Scale, a cogni- increase in IADL score was not significant. As noted tive subscale (ADAS). These improvements were opera- from previous studies conducted to assess Alzheimer’s tionalized as a smaller decline in cognitive functioning medications (Johannsen et al., 2006), it is possible that Inkblot: The Undergraduate Journal of Psychology • Vol. 2 • September 2013 | 47 the effect of tacrine slowing cognitive deterioration promising results lead to further research, however, may have concurrently slowed the negative effects of Racetam medications could be offered as clinical treat- Alzheimer’s disease on participants’ quality of life. The ment options, and patients could have access to an in- literature suggests that tacrine treatment does not influ- expensive compound more efficacious in the treatment ence improvement in cognitive abilities and quality of of Alzheimer’s disease than the currently used medica- life in patients with Alzheimer’s disease, but is useful in tions. In order to counter the weaknesses of previous slowing down the cognitive deterioration caused by the studies, future research on these reviewed medications (donepezil, tacrine, and the Racetam compounds) should use larger sample sizes, observe the drug effects over a longer period of time, and compare the effects of different medications directly against each other using a single study design. Studies of high methodological The deterioration of cognitive ability is one of quality -- having those characteristics of which were de- the main symptoms of Alzheimer’s disease. It appears scribed above, including a large sample size ─ replicat- that current medications (i.e., donepezil and tacrine) ed multiple times, are needed to wade out any positive slow the deterioration of cognitive abilities while ani- results that may occur due to chance. Also, given that racetam and oxiracetam appear to improve cognitive these studies are dated (Bottini, et al., 1992; Maina, et abilities above baseline. Studies conducted with ani- al., 1989; Dager, et al., 1992; Davis, et al., 1992; Gouliaev racetam demonstrate the drug’s ability to reverse the & Senning, 1994; Green, et al., 1992; Knopman, et al., cognitive deterioration caused by Alzheimer’s disease 1996; Senin, et al., 1991), newer, more validated, and re- (Senin, et al., 1991). Oxiracetam appears to have the liable neuropsychological tests should be administered most substantiating evidence in favour of its ability to concurrently with the administration of oxiracetam and reverse the effects of Alzheimer’s disease. It not only aniracetam to better assess their effects.
halts the progression of Alzheimer’s disease, but also Oxiracetam and aniracetam are currently sold at improves the patient’s cognitive abilities (Senin, et al., $649 USD and $329 US per kg, respectively (Cerebral- 1991). The literature suggests that these improvements Health, n.d.). At the doses used in the cited studies of in cognitive ability mostly pertain to memory ability 1600mg/day and 1500mg/day, the price of oxiracteam (i.e., semantic, recognition, short term, and associative and aniracetam administration per day would be $1.04 memory), attention, abstract reasoning, executive func- USD and $0.49 USD, respectively. These prices contrast tioning, and concentration (Bottini et al., 1992; Maina, with Aricept at $8.03 USD, and tacrine at $8.03 USD, et al., 1989; Senin, Abate, Fieschi, and Gori, 1991; Vil- per day (DrugBank, 2011). Despite the lack of research lardita et al., 1992). Thus, evidence suggests that Race- surrounding differences in these medications, it is ap- tam compounds are equal y, or more, efficacious in the parent that the Racetam compounds are much cheaper treatment of Alzheimer’s disease in comparison to the than the other drugs discussed in this paper. As pre- viously stated, no studies have compared the Racetam drugs with donepezil or tacrine, and consequently, di- rect comparisons of drug efficacy are difficult. When Despite oxiracetam and aniracetam’s relatively considering the large price difference in these drugs, superior therapeutic effects on patients, no study com- common sense would suggest that the more expensive paring the therapeutic efficacies of Racetams to those compound be more efficacious in reducing Alzheimer of donepezil and tacrine have been conducted. If these symptoms. However, this literature review did not find 48 | Inkblot: The Undergraduate Journal of Psychology • Vol. 2 • September 2013 that the more expensive medication was more effective. As discussed, the Racetam compounds appear to pro- vide a greater benefit to the patients in the studies dis- Aricept. (2011). Aricept Home. In Aricept. Retrieved cussed in this paper (Bottini et al., 1992; Maina, et al., 1989; Senin, Abate, Fieschi, and Gori, 1991; Vil ardita et Bottini, G., Val ar, G., Cappa, S., Monza, G. C., Scar- al., 1992) than either donepezil or tacrine (Johannsen, pini, E., Baron, P. & Scarlato, G. (1992). Oxiracetam in dementia: a double‐blind, placebo‐controlled study. Acta Neurologica Scandinavica, 86(3), 237-241.
Dager, S. R., Loebel, J. P., Claypool, K., Case, M., Budech, C. B., & Dunner, D. L. (1992). Oxi- the treatment of Alzheimer’s disease. They are well tol- racetam in the treatment of primary dementia erated by patients and exhibit significant therapeutic of the Alzheimer’s type: A small case series. efficacy. In comparison to current medications, studies International Journal of Geriatric Psychiatry, suggest that Racetam compounds are either equal y, if not more, effective in inducing improvements in cog- Davis, K. L., Thal, L. J., Gamzu, E. R., Davis, C. S., nitive ability and quality of life. These compounds are Woolson, R. F., Gracon, S. I., . . . Doody, R. S. an inexpensive alternative to current medications. De- (1992). A double-blind, placebo-controlled spite showing positive results in the use of Alzheimer’s multicenter study of tacrine for Alzheimer’s disease and dementia, Racetam research is lacking. Pre- disease. New England Journal of Medicine, scribing Racetam compounds may cause the reversal or retardation of some of the symptoms of the disease DrugBank. (n.d.). DrugBank. In DrugBank Open Drug seen in patients. Thus, future research on Alzheimer’s & Drug Target Database. Retrieved March disease and other forms of dementia should also focus 29th, 2012, from
on Racetam compounds, to assess whether the effects of Gatz, M., Reynolds, C. A., Fratiglioni, L., Johansson, previous treatments were valid or due to chance. B., Mortimer, J. A., Berg, S., . . . Pedersen, N. L. (2006). Role of genes and environments for explaining Alzheimer disease. Archives of general psychiatry, 63(2), 168-174.
Gouliaev, A. H., & Senning, A. (1994). Piracetam and other structural y related nootropics. Brain Research Reviews, 19(2), 180-222.
Green, R. C., Goldstein, F. C., Auchus, A. P., Pres- ley, R., Clark, W. S., Van Tuyl, L. & Karp, H. R. (1992). Treatment trial of oxiracetam in Alzheimer’s disease. Archives of Neurology, Johannsen, P., Salmon, E., Hampel, H., Xu, Y., Rich- ardson, S., Qvitzau, S., & Schindler, R. (2006). Assessing therapeutic efficacy in a progressive disease. CNS Drugs, 20(4), 311-325.
Inkblot: The Undergraduate Journal of Psychology • Vol. 2 • September 2013 | 49 Kenda, B, & Matagne, A. (2012). US Patent Applica- diencephalic-lesioned rats. (Masters Disserta- Knopman, D., Schneider, L., Davis, K., Talwalker, S., tion). Retrieved from ProQuest Dissertations Smith, F., Hoover, T., & Gracon, S. (1996). and Theses Database. (UMI# 1432084).
Long-term tacrine (Cognex) treatment effects Senin, U., Abate, G., Fieschi, C., Gori, G., Guala, A., on nursing home placement and mortality. Marini, G. & Parnetti, L. (1991). Aniracetam Neurology, 47(1), 166-177.
(Ro 13-5057) in the treatment of senile de- Maina, G., Fiori, L., Torta, R., Fagiani, M. B., Ravizza, mentia of Alzheimer type (SDAT): results of a L., Bonavita, E. & Macciolli, D. M. (2008). placebo controlled multicentre clinical study. European Neuropsychopharmacology, 1(4), degenerative and multi-infarct dementia: a double-blind, placebo-controlled study. Neu- Vil ardita, C., Grioli, S., Lomeo, C., Cattane, C., & ropsychobiology, 21(3), 141-145.
Parini, J. (2008). Clinical studies with oxirace- National Institutes of Health. (n.d.). National Institutes tam in patients with dementia of alzheimer type and multi-lnfarct dementia of mild to Health. Retrieved from moderate degree. Neuropsychobiology, 25(1), Roland, J.J. (2003). Hippocampal and striatal acetyl-


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