Comparative safety and effectiveness of cholinesterase inhibitors and memantine for Alzheimer’s disease: a network meta-analysis of 41 randomized controlled trials

Abstract

BackgroundCholinesterase inhibitors and memantine have been approved for management of Alzheimer’s disease (AD), but there has been no consensus about the choice of various types and doses of drugs at different stages. Hence, we compared and ranked the efficacy and tolerability of these available drugs.MethodsWe searched PubMed, the Cochrane Central Register of Controlled Trials, and Embase for randomized controlled trials (RCTs) published from database inception to July 21, 2017. The primary outcomes were the mean overall changes in cognitive function and responders who had any adverse events. We conducted a random-effects network meta-analysis.ResultsForty-one RCTs were included in this study. Compared with placebo, galantamine 32 mg daily (standardized mean difference – 0.51, 95% credible interval – 0.67 to − 0.35), galantamine 24 mg daily (− 0.50, − 0.61 to − 0.40), and donepezil 10 mg daily (− 0.40, − 0.51 to − 0.29) were probably the most effective agents on cognition for mild to moderate AD, and memantine 20 mg combined with donepezil 10 mg (0.76, 0.39 to 1.11) was recommended for moderate to severe patients. Memantine showed the best profile of acceptability. Rivastigmine transdermal 15-cm2 patch was the best optional treatment both in function and global changes. None of the medicines was likely to improve neuropsychiatric symptoms through this analysis.ConclusionsPharmacological interventions have beneficial effects on cognition, function, and global changes, but not on neuropsychiatric symptoms, through current network meta-analysis. The choice of drugs may mainly depend on the disease severity and clinical symptoms.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0457-9) contains supplementary material, which is available to authorized users.

Regulation of cholinergic basal forebrain development, connectivity, and function by neurotrophin receptors

“…Whether an even distribution of axonal innervation across the cortex would suffice is unknown, although the evidence presented above regarding the precision of cholinergic innervation linked to function would suggest not. However, acetylcholineesterase inhibitors such as Aricept show mild to moderate efficacy even when the specificity of timing and/or neuronal response cannot be maintained by this class of drug [212,213]. Therefore, it remains to be demonstrated whether specific timing of and/or a precise location of axonal innervation and acetylcholine release in the cortex is required for efficacious neurotransmission, and whether neurotrophins or mimetics can be used to enhance cholinergic-based treatment avenues for dementia.…”

Alzheimer’s Disease Pharmacotherapy in Relation to Cholinergic System Involvement

“…Centrally mediated acute gastrointestinal events (especially nausea and vomiting) are class side effects of all ChEIs with the dual AChE and BuChE action and are described mainly throughout the dose-escalation phase of the treatment. Instead, these effects can be minimized by using slow dose escalation with low dose gradations and administering them with food [81]. The side effects of ChEIs registered frequently during the maintenance phase of therapy include central nervous system signs; extrapyramidal events; sleep disorders and cardiorespiratory disturbance related to cholinergic action in the cortex, caudate nucleus of the basal ganglia, brainstem, and medulla; cardiorespiratory symptoms and urinary incontinence in relation to peripheral cholinergic action [19,25].…”

“…ChEIs are well tolerated; patient's compliance and caregiver suitability are good when dosed with care. The promising tolerability and safety profiles of these compounds make them appropriate first-line therapy strategies for AD [18,81].…”

Improving Anti-Neurodegenerative Benefits of Acetylcholinesterase Inhibitors in Alzheimer’s Disease: Are Irreversible Inhibitors the Future?

“…Both clinical efficacy and adverse events induced by AChE inhibitors are dose-dependent [123], which indicates that high-level CNS AChE inhibition (above 50%) [69] will likely improve efficacy if the problem of adverse events can be overcome [69,124]. Increased CNS AChE inhibition, above what is currently available, will also improve the "CSF Cholinergic Index", an in vivo physiological measure of an improved CNS ratio of AChE inhibition compared to increased choline acetyltransferase in AD patients [125].…”