AD is a progressive, debilitating disorder estimated to affect some 5-10% of people over 65 years old and as many as 50% of those over 85 years of age.[13
] The cognitive deficits are responsible for progressive impairment in activities of daily living such as driving, buying groceries, preparing meals, doing laundry and basic functions such as walking safety and maintaining personnel hygiene[14
] AD is characterized by deficits in memory and cognition that are associated with significant losses of presynaptic cholinergic function in the brain, particularly the nucleus basalis of Meynert.[15
] Bartus et al
proposed the cholinergic hypothesis of AD suggesting that the deficiency of the neurotransmitter, acetylcholine, in the brain could be amenable to replacement therapy.[16
Donepezil hydrochloride is a potent, reversible, and highly selective inhibitor of AChE, and as a piperidine-based agent, chemically distinct from the other ChE inhibitors.[1
] The efficacy and safety of donepezil has been demonstrated in patients with AD through various global, double-blind, and open-labeled studies ranging from 12 weeks to 5 years duration.[19
] Though donepezil is available in India since 2002, to the best of our knowledge, there are no studies evaluating the safety and efficacy in the India population.
The present study evaluated the safety and efficacy of donepezil hydrochloride in Indian patients suffering from mild to moderate AD. Progressive cognitive impairment is the hallmark of AD. In the present study, MMSE was used to evaluate cognition, as it is the most common instrument used by clinicians in their day to day practice in evaluating and managing patients with AD. Patients with AD are likely to have a relative preservation of long term memory, especially in the early stage of the dementia and greater deficits in frontal executive functioning like planning, organization, abstraction, category fluency initiation, reasoning, mental flexibility, sequencing, fine motor performance, and the allocation of attentional resources than patients with AD.[24
] Significant improvement in MMSE was observed from as early as 4 weeks of study period (P
The findings of the present study are consistent with the findings reported by Klinger T et al
] and Relkin N et al
] In the study conducted by Klinger T et al
, which was a post-marketing surveillance study conducted on 913 patients with mild to moderate AD in Germany, patients who were not satisfied with existing anti-dementia medications and those who were treatment naïve were treated with donepezil 5 mg for 4 weeks. In the present study, patients showed a significant improvement in cognition as evaluated on MMSE by 2.21 (± 3.47) points at the end of 12 weeks. In the study conducted by Relkin N et al
(2003), cognition was evaluated in patients with mild to moderate AD over 12 weeks period on standardized version of MMSE (sMMSE). At the end of 12 weeks, there was an improvement in cognition by 1.54 (± 3.05) points on sMMSE.
Studies of 6 months duration in patients with mild to moderate AD treated with donepezil have demonstrated the improvement on cognition to persist even at end of six months[27
] and long term studies have demonstrated the improvement in cognition on Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) to be above baseline values for as long as 38 weeks and at any point-of-time retained better than the placebo in long term studies over 5 years of duration.[29
The early symptoms of AD involve difficulty with the episodic memory, the ability to encode information and later recall.[1
] There is visuospatial impairment evident on the inability to make drawings and other constructions or to orient themselves to their surroundings. Also, affected in AD is language, with initial word finding difficulty progressing to anomia and impaired comprehension. Early in the disease course, there may be an inability to retrieve words with circumlocution and poor wordlist generation, particularly for words in the given semantic category. As disease progresses, difficulty naming becomes apparent and spontaneous speech becomes increasingly empty.[30
] Hence, improvement in cognition noted in the present study on MMSE and individual cognitive domains reflects a significant benefit in the real world setting from the patient's perspective when we relate to a progressive disorder like AD. When individual components of MMSE were analyzed, it demonstrated a trend for improvement in all the components of MMSE with significant improvement in orientation, attention, and recall in this group of patients.
The mean 3.05 point improvement from baseline in total MMSE scores for the evaluable population confirms that the cognitive benefits of donepezil observed in controlled studies can also be measured in routine clinical particle. These findings are consistent with the findings reported study conducted by Rockwood K et al
] In this multi-center, 6-month, open-label study of 101 primary care patients, changes in a 19-symptom checklist were assessed in relation to changes in standardized scales of cognition, activities of daily living, behavior, and caregiver burden and the clinicians reported significant improvement in cognitive symptoms like recall, attention, and spatial and temporal orientation over 12 and 24 weeks of study period.
Deterioration in functional abilities of daily living has a major impact on quality of life of an individual with AD.[30
] Feelings of incompetency and loss of control are often expressed by the dementia victim in the earlier stages of the disease.[30
] Functional deficits starts to occur at a stage when cognition deficits are mild and first become apparent in complex occupational tasks, such as work or hobbies and in social activities like forgetting appointments, difficulty in finding their way home, preparing meals, using telephone, etc. When cognition deficits become moderately severe, individuals start experiencing difficulties with basic activities of daily living like increasing ability to dress, bathe, and toilet. Deterioration in functional abilities has important effects on the life of individual with AD as well as on caregiver.[32
In the present study, there was a significant improvement in ADL index and individual component analysis of ADL index in 13 of 17 domains of ADL index scale. More than 20% of the patients’ demonstrated improvement in either of the activities of daily living as measured on the ADL index scale. There was an improvement in dressing, washing, bathing, using lavatory and continence. Activities like grooming, brushing teeth, preparation for making tea, making tea, using taps and feeding also improved with donepezil. Similar findings were noted in the study conducted by Rockwood K et al
in which ≥20% of patients reported improvement in domains of judgment, hygiene, dressing, and domestic activities.[33
The findings of global assessment in the present study are similar to those reported Klinger T et al
wherein the investigators assessment of safety was reported between very good to good in 93.5% of total patient populations.[34
All the patients exhibited good patient compliance with >98% of patients being complaint throughout the study period.
The study drug was well tolerated in the present study with most of the adverse events being mild to moderate in intensity and not requiring discontinuation of study medication. Most of the adverse events were reported in the first 4 weeks of study period. In the study conducted by Relkin N et al
(2003), the common adverse events reported were anorexia, diarrhea, nausea, abdominal disturbances, vomiting, generalized weakness, agitation, confusion, dizziness, and headache.[35
The incidences of cholinomimetic properities of donepzil in the present study are highly consistent with the known tolerability profile of donepezil.[36
] This low rate of adverse events may be partly attributed to the specificity of donepezil for AChE in the central nervous system. Donepezil significantly inhibits brain AChE, while having little effect on either the cardiac muscle or smooth muscle.[38
While the present study extends the available data on tolerability of donepezil to the Indian population that is more community dwelling patients, it has its own limitations. Patients with unstable medical or psychiatric conditions were excluded from this study. However, these exclusions are consistent with safe medical practice and do not necessarily constitute limitations to this study. This was an open-labeled study, which introduces the possibility of rater bias in the assessment of efficacy. Nevertheless, the statistically significant improvements in cognitive function that were observed in patients treated with 5 and 10 mg/day of donepezil are consistent with those observed in previous double-blind, placebo-controlled studies and the post marketing surveillance studies conducted in Germany. This suggests that the efficacy of donepezil measured in pivotal trials worldwide can still be obtained in Indian patients, despite administration of a variety of concomitant medication.
Another limitation of the present study is its shorter duration. Three months was chosen as the minimum period of the study, since this enables the evaluators to establish first impressions of efficacy and safety data in the Indian patients without compromising the quality of the data due to attrition that can occur with longer trials in AD.
Based on the results reported, the present study offers support for the safety and efficacy of donepezil in the treatment of elderly, community-dwelling Indian patients with mild to moderately AD.