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Cognition enhancing effects of donepezil in traumatic brain injury


Effects of donepezil, an AchE inhibitor widely prescribed in Alzheimer’s disease, on cognitive functions after TBI, have already been suggested in some studies. Taverni et al.15 reported improved memory and increased alertness in 2 TBI patients following 3 weeks of donepezil administration. However, this study lacked both a prospective design and validated neuropsychological tests. In another study 16 , 7 TBI outpatients showed 5 or more points of improvement on the Mini Mental State Examination (MMSE) after donepezil therapy. Whelan et al. 17 investigated the long term effects of donepezil in a group of 22 TBI patients. Results after 13 months of treatment indicated an improvement in full scale IQ score as well as in clinician based ratings of function. Masanic et al. 2 explored the effects of 12week donepezil treatment on 4 patients with severe chronic TBI (5 mg daily for 8 weeks and 10 mg daily for 4 weeks). Their results showed significant improvement in memory tests and a positive trend in neuropsychiatric scales. In another report, donepezil administration to a TBI patient improved MMSE score (from 18 to 23), which was already evident after 10 days 18 . A review of several studies 15 presented evidence for the benefit of cholinergic agents in treating cognitive (memory and attention), and possibly behavioural impairment, following TBI. Finally, a recent study showed an improvement in short term memory and sustained attention following 10 weeks of treatment in 18 chronic TBI patients


Some patients complained of nausea, sleep disorders, anxiety, excitability, cramps and dizziness. As already mentioned, 4/15 patients (all women) interrupted donepezil intake after 1 week due to the side effects. Concerning the other patients who continued the treatment, those who have also suffered from some of these side effects described their total disappearance within 2 or 3 weeks following medication. Subjects’ SelfEvaluation after Treatment A majority of patients (8/10) described a medication related improvement in at least one cognitive or affective behavioural domain. As detailed in table 1, positive changes could be observed in all investigated domains, with a most dominant effect in the fatigue sphere (4/10 patients). It is noteworthy that such positive changes have also been noticed by several collaterals, most often by the spouse (as reported by the patients themselves). These modifications appeared to have a positive impact on daily activities (professional activities, hobbies and studies). For instance, some patients reported enhanced performances in reading, studying, and working, particularly by improving their organizational aptitudes. None of the patients who had interrupted their professional activity following the accident could resume this activity following medication, although they described an improvement in tasks undertaken beforehand. The most important change was observed in patient No. 3 (table 1) who could not read (due to attention difficulties) or take guitar lessons after the accident and who successfully took up these activities following donepezil treatment. With respect to negative effects, only patient (No. 2) complained about increased anxiety and excitability. However, despite the fact that she reported positive changes only in the fatigue sphere, her scores improved on almost all neuropsychological tests (not detailed).


Affective Behavioural Changes Concerning the affective and behavioural domains, the patients globally described an enhancement in energy and a decrease in apathy. Analysis of patients’ mean scores on the different questionnaires (anxiety, depression, fatigue and dysexecutive scales) revealed a slight improvement in all investigated domains (table 2), particularly in depression. The comparison of the global score of all questionnaires before and after therapy revealed a marginally significant effect (Wilcoxon matched pairs test, Z = 1.90, p = 0.058 Neuropsychological Results Inspection of the neuropsychological mean scores showed a slight improvement in several tests or subtests (table 3). In executive functions’ tests, a significant change concerned speed of processing in Stroop colour naming subtest. With respect to learning and memory tests, a positive change was found in the learning phase of the RAVMT test as attested by an increased number of immediately recalled words (fi g.1 a). Finally, the computerized divided attention task, which addressed more specifically the patients’ ability to simultaneously perform two different tasks that engage two sensorial modalities, demonstrated a significant decrease in the number of errors following treatment with donepezil ( fi g. 1 b). Of note here is the fact that this improvement was not attributable to a speed/accuracy tradeoff since it was not accompanied by a prolongation of response time in the same test


Concerning the tolerability of donepezil in TBI patients, it appeared, as has been previously suggested 30 , to be relatively good. Collateral effects motivated interruption of medication in 4/15 subjects of the recruited sample. Subjects who experienced side effects, but nonetheless continued treatment, reported the disappearance of their symptoms within 2 or 3 weeks. However, it is worth noting that side effects appeared to be of more importance in this population than in healthy controls where Donepezil administration induced adverse events in only 10% of the subjects 31 . In the affective behavioural domain, posttreatment evaluation showed only a slight global improvement. This improvement most notably involved the depression dimension, but without affecting anxiety symptoms. It is worth mentioning that 1 patient complained of enhanced excitability, irritability and anxiety, but simultaneously reported increased motivation and energy. These observations corroborate previous reports indicating that, while depression and apathy could positively be affected by donepezil therapy, irritability and agitation remained unaffected2,32. The subjective improvement of fatigue in 4 patients did not systematically correlate with the slight decrease in the global fatigue index. Actually of these 4 patients, only 2 showed a notable decrease on fatigue score (patients 1 and 4). On the other hand, 2 other patients did not subjectively report improvement on fatigue although they showed a clearly significant decrease on the fatigue scale (patients 6 and 7). These discrepancies are not surprising when considering the popular knowledge of fatigue33 that contrasts with more operational definitions such as failure to maintain a required output during a given task. Subjective decrease in fatigue may also be related to the improvement of attentional capacities34, which are generally affected after TBI. Indeed, 5 patients expressed significant better functioning in occupational and other everyday activities necessitating attention skills (e.g. reading or playing an instrument, studying or planning in work). At the cognitive level, several patients subjectively reported improvement in at least one cognitive domain. Neuropsychological results indicated a slight improvement in several tests. The significant changes concerned speed of processing in the Stroop colour naming task, learning in the RAVMT and a performance in the divided attention test. In addition to their participation to brain activation systems, cholinergic projections have repeatedly been identified as being involved in learning, memory and attention processes35. With respect to learning, microdialysis experiments in the rat showed an increased release of cortical acetylcholine during early acquisition stages when attentional demands are high36, thus suggesting that cholinergic transmission might not be important for encoding per se, but for modulating its attentional components. In line with these data, our findings suggest that enhancement of cholinergic transmission in TBI patients might positively affect attention and memory and thus corroborate the results of previous studies using donepezil2,7,15. Due to the size of the investigated sample, this study did not seek to control the treatment by imposing a placebo arm with a control group. Although the observed changes can unlikely be explained by spontaneous recovery due to the fact that all patients were in a chronic phase, it is difficult at this stage to completely disentangle the effects of global support (placebo effects) and the specific effect of donepezil. The fact that the clinical improvement in everyday functioning appeared as the most notable aspect, cannot exclude the hypothesis of a benefi cial effect of global support. However, the improvement in learning/memory and attention, the major cognitive domains classically targeted by AchE inhibitor therapies, favour the hypothesis of a specific beneficial effect of donepezil on cognition. Based on these observations, we suggest that donepezil may represent a suitable therapeutic option for TBI patients

A pilot study of brain morphometry following donepezil treatment in mild cognitive impairment: volume changes of cortical/subcortical regions and hippocampal subfields


Changes in symptom severity

The average KMMSE scores in healthy controls (n = 9), untreated patients (n = 10, baseline), and donepeziltreated patients (n = 10, followup) were 28.6 ± 1.1, 16.3 ± 4.9, and 17.6 ± 3.5, respectively (Table 1). We found a significant difference in the KMMSE (p = 0.031) between untreated patients and donepeziltreated patients, in which the average scores were improved following donepezil treatment. Also, it should be noted that the average scores on the ADASCog in untreated and donepeziltreated patients were 25.3 ± 8.0 and 25.1 ± 6.1, respectively (p = 0.759, NS); the average scores on the CDR in both groups were 0.7 ± 0.2 and 0.6 ± 0.2, respectively (p = 0.157, NS) and the scores on the GDS were 13.0 ± 5.0 and 12.6 ± 4.8, respectively (p = 0.370, NS) (Table 1).


Global GM volume changes in three groups

Compared with healthy controls (n = 9), both of the untreated (n = 10) and treated (n = 10) patients showed significantly reduced GM volumes in the bilateral hippocampus (FWE corrected, p < 0.05, Fig. 2). As for the comparison between untreated and treated patients with 6month donepezil therapy, the treated patients showed significantly higher GM volumes in the putamen, globus pailldus, and inferior frontal gyrus after (uncorrected; p < 0.001; Fig. 3a), and concurrently showed lower GM volume in the left hippocampus (uncorrected; p < 0.05; Fig. 3b


Hippocampal and its subfield volume changes

Volumes of the hippocampus in healthy controls, untreated patients, and donepezil treated patients were 7,724.8 ± 513.6, 6,312.1 ± 731.4, and 6,277.0 ± 654.5 mm2, respectively (HC vs. baseline: p = 0.006, HC vs. follow up: p = 0.004, baseline vs. follow up: p = 0.721). The average hippocampal volumes in the untreated and treated patients are lower than that in healthy controls. However, the hippocampal volumes of untreated patients and treated patients were not significantly different from each other.


As shown in Fig. 4, the untreated patients showed significantly reduced volumes in the right subiculum and left CA3 compared with healthy controls (Bonferroni corrected, p < 0.05, Table 2). The treated patients also showed reduced volumes in the right subiculum and right CA1 compared with healthy controls (Bonferroni corrected, p < 0.05). However, the hippocampal subfield volumes of untreated patients and treated patients were not significantly different (Table 3). Interestingly, the rate of volume change in the left hippocampus in untreated patients was negatively correlated with the period of treatment (rho = 0.80, p = 0.005, Fig. 5


MRI based volumetry of the hippocampus has been proposed as a useful tool for the clinical diagnosis of AD3,23. Among the characteristic neuropathological changes seen in AD, the most prominent structural changes at the initial stage occur in hippocampal formation3,24. In our study, both of the patients with MCI showed GM atrophy in the lateral hippocampus compared with healthy controls. We also found that the untreated patients had significantly lower scores on the KMMSE as compared with healthy controls.


Figure 4 compared the hippocampal subfield volumes between three groups. In comparison with healthy controls, the untreated patients showed significantly reduced volumes in the right subiculum and left CA3, whereas the treated patients showed reduced volumes in the right subiculum and right CA1. Although the treated patients showed reduced volumes in the left CA3 (p = 0.005), the pvalue is not significant at the 0.5 level (p = 0.003) of Bonferroni correction. The hippocampal subfields atrophy has been shown to be implicated in the progression of AD. Especially, volume of the left subiculum was correlated with the performance score across auditory verbal learning test measures20. Also, atrophy in the subiculum and CA1 was strongly associated with AD diagnosis, and furthermore, such a strong correlation with hippocampal subfields is most predictive of future conversion from normal controls to MCI and MCI to AD25. Here, it is suggested that specific hippocampal subfield atrophy is closely related with MCI and/or early stages of AD.


Compared with untreated patients, the donepezil treated patients showed significantly higher scores on the KMMSE as well as increased GM volumes in the putamen, globus pallidus, and inferior frontal gyrus (Fig. 3). However, a volumetric increase attributable to donepezil treatment was not observed in the hippocampus, which is contrary to the finding in a previous study11. Nevertheless, Hashimoto et al.3 have suggested that the mean annual rate of hippocampal volume loss in donepezil treated patients is significantly less than that in control patients. In our study, however, we did not find increased hippocampal subfield volumes in patients after 6 months of donepezil treatment. Also, the whole volume of the hippocampus volume decreased by 0.6% after 6 months of donepezil treatment. Also, note that the rate of volume change in the left hippocampus was negatively correlated with the period of treatment (Fig. 5).


Increases in the local GM volumes as seen in our study could be associated with a restoration of cell number induced by to donepezil treatment, an indirect neurotrophic effect on the neuropil, or both. Kotani et al.26 have suggested that donepezil activates central cholinergic transmission and thereby enhances the survival of newborn neurons in the dentate gyrus in a rat model. In another similar study27 with a rat model of vascular dementia demonstrated that the efficacy of donepezil treatment induced an increase of the expression of brain derived neurotrophic factor (BDNF). Consistent with this finding, patients with early AD showed an increase in BDNF serum concentration after donepezil treatment28. The BDNF has been demonstrated to contribute to increased beta amyloid degradation by promoting the expression of somatostatin28,29. Accumulations of beta amyloid is one of the earliest changes in AD pathology and may cause neuronal death in the central nervous system (CNS)3,30. Preventing this is a second way in which BDNF may increase neuron numbers relative to untreated control patients. Moreover, BDNF belongs to the nerve growth factor family and plays important roles in neuronal survival, differentiation, and synaptic plasticity in the CNS28, suggesting that it may also expand neuropils by a neurotrophic effect.


In this current study, we found that compared with untreated patients, donepezil treated group showed significantly increased GM volumes in the putamen, globus pallidus, and inferior frontal gyrus which are involved in improved cognitive function. A previous study31 demonstrated that, compared with a patient group with AD having a 2point increase in the MMSE following nine month donepezil treatment, another patient group having a 2 point decrease showed significantly reduced GM volume in the putamen. In our study, however, donepezil treated patients having a 1.3 point increase in the KMMSE following six months treatment showed markedly increased GM volume of the same brain area in comparison to the untreated patients. The putamen is best known for its role in the planning and modulation of movement pathways, and is potentially involved in a variety of cognitive processes involving executive function, such as working memory32. In addition, putamen function is linked to a variety of neurotransmitters such as acetylcholine33, and this brain area is potentially associated with the improved cognitive function. Another important brain area showing sparing by donepezil treatment is the inferior frontal gyrus. De Lange et al.34 reported that patients with chronic fatigue syndrome showed significant increases of GM volume in the inferior frontal gyrus after cognitive behavioral treatment. Here, it is important to note that the relationship between specific GM volume increment and enhanced KMMSE score in treated MCI patients might be not clearly explained because of the retest effect in KMMSE.


This study has some limitations. First, the population of subjects is small, leading to a lower statistical power. To compensate this disadvantage, we used a statistical threshold of P value less than 0.05 using the Bonferroni correction, giving a statistically reliable significance level. Future studies with larger numbers of subjects are needed. Second, healthy control group was not followed up for the KMMSE, ADAScog, CDR, and GDS after 6month time frame equivalent to the treatment period. Third, we need further study on the comparison of the volume changes among mild vs. moderate vs. severe levels in AD with respect to the effects of donepezil treatment. Fourth, additional to brain morphometry, the combined multimodal imaging techniques including functional MR imaging, MR spectroscopy and positron emission tomography are needed to gain more valuable information on the functional activation and connectivity and cerebral metabolic changes in connection with therapeutic effect.



This study has demonstrated variations of the gray matter volumes in the cortical and subcortical regions and hippocampal subfields after donepezil treatment in patients with MCI. Untreated MCI showed lower GM volumes in the hippocampus and its subfields, specifically in the right subiculum and left CA3 when comparing to healthy control. However, the hippocampal subfield volumes of untreated and treated patients were not significantly different from each other. These findings will be helpful to understand the pathogenesis of MCI as a prodromal phase of AD in connection with the morphometric changes of specific brain areas

The effectiveness of donepezil for cognitive rehabilitation after traumatic brain injury: a systematic review


To summarize, our review of the literature on the use of donepezil for the treatment of cognitive impairments sustained after TBI suggests the possibility of its efficacy, but does not drive us to support its use uncritically. The bottom line is that the effectiveness of donepezil on cognitive rehabilitation after TBI remains uncertain owing to the scarce evidence so far obtained, and the poor methodological quality of the studies (see Table 2). The efficacy and safety of donepezil in treating cognitive dysfunction after TBI does not seem to be different from other AChEIs such as galantamine and rivastigmine.11Regarding safety, whereas noncomparative trials present evidence for the appearance of non negligible cholinergic and behavioral adverse effects, which seem to be dose dependent on donepezil,14,16,17,19,21 comparative trials do not report such problems. A single case of severe adverse effect has been reported so far in anRCT.10This discrepancy could be the result of the different TBI populations assessed in the different trials(there seem to be more severe impairments included in the noncomparative trials than in the comparative designs), the different time window in the prescription of donepezil (comparative trials include mainly acute rehabilitation programs, whereas most noncomparative designs assessed donepezil in post acute rehabilitation programs), or other characteristics such as maximum daily dosage attained for donepezil. Additional larger RCTs of good quality are needed to substantiate beyond any reasonable doubt the off label indication of donepezil (and other AChEIs)in the treatment of cognitive impairments following TBI


Donepezil (Aricept) and memantine (Namenda) are FDAapproved for the treatment of Alzheimer’s dementia. Aricept works by increasing a chemical in the brain called acetylcholine that is important for memory and learning. Namenda blocks a chemical in the brain called glutamate.


Several studies have evaluated Aricept for memory problems after traumatic brain injury and have found it effective. Namenda has fewer studies but there is also some evidence it may give help with memory disorders after traumatic brain injury. The studies showed, however, that the benefits of both medications were more evident in people with more severe impairment. Neither took away the memory problems but in some people, the drugs improved memory, learning, and behavior. Both medications have side effects that need to be monitored by a medical professional. These medications can have a role as part of a comprehensive treatment program for memory, attention, concentration, mood and behavior.

donepezil and memantine






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