Glutamate Modifiers

Memantine

A growing body of evidence suggests that disturbances in glutamatergic neurotransmission may underlie the neurobiology contributing to the cognitive deficits seen in patients with AD. Approximately 70% of synapses in the brain use the excitatory neurotransmitter glutamate. Physiologic levels of glutamate are essential for processes such as learning and memory. However, abnormal glutamate levels, as seen in Alzheimer’s disease, can lead to sustained, low-level activation of the NMDA receptors and thereby cause neuronal toxicity and cognitive deficits. Normalization of glutamatergic neurotransmission may maintain or improve cognition and prevent neurotoxicity.²⁹

The destructive effects of glutamate are mediated primarily by the N-methyl-D-aspartate (NMDA) receptors.²⁹  Pathologic activation of NMDA receptors takes place as a result of excessive amounts of glutamate, even at rest. Long-term displacement of the Mg²⁺ ion from the NMDA receptor occurs, and the influx of Ca²⁺ ions into the cell is constant.  Sustained leakage of Ca²⁺ ions into the cell is associated with the cell damage, impaired learning, and premature cell death associated with Alzheimer’s disease. 

Memantine, a voltage-dependent, uncompetitive NMDA receptor antagonist, modulates the intracellular activity of glutamate. With its low to moderate affinity for the NMDA receptor, memantine does not cause the deleterious neuropsychiatric effects associated with the use of other, high-affinity NMDA receptor antagonists, such as ketamine and amantadine. Moreover, the fast on/off kinetics of memantine enable the drug to block the effects of abnormal glutamate activity under pathologic conditions but preserve physiologic activation of NMDA receptors required for learning and memory.²⁹

Memantine has been used in Europe since the 1980s for the treatment of various neurologic disorders, including vascular dementia and Parkinson’s disease. In October 2003, the drug was approved in the United States for the treatment of moderate to severe dementia of the Alzheimer’s type.

Memantine exhibits 100% bioavailability with low (45%) plasma protein binding and achieves peak plasma concentration 3-7 hours after oral intake. The drug is rapidly distributed to the brain and is able to cross the blood-brain barrier. Memantine undergoes limited hepatic metabolism, with minimal effects on P450 isoenzymes, and is eliminated primarily via the kidneys. Its use in patients with severe renal impairment has not been studied and therefore should be avoided. Dose reductions in patients with moderate renal impairment should be considered.³⁰ Importantly, drug interaction studies and post-marketing surveillance data from Germany indicate that memantine does not alter the activity of acetylcholinesterase. The drug, therefore, may be used in combination with acetylcholinesterase inhibitors. Thus, memantine represents an important addition to the currently available treatment options for Alzheimer’s disease.

Reisberg and colleagues³¹ conducted a 28-week double-blind, placebo-controlled phase III study in 252 outpatients with moderate-to-severe Alzheimer’s disease (mean Mini-Mental State Examination [MMSE] score, 7.9 + 3.64; range, 3-14). Memantine treatment was given in a standard 4-week titration increased weekly in 5-mg increments from 5 mg to 20 mg daily, with the final dose being 20 mg a day dispensed as 10 mg twice a day. Principal efficacy measures were the Severe Impairment Battery (SIB), the Clinical Interview-Based Impression of Change with caregiver information (CIBIC-Plus), and the Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, which measures 19 domains of function. Global assessment was recorded using the CIBIC-Plus, which is an examination of the patient done by the clinician with input from the caregiver.

The completion rates were 77% for the memantine group and 67% for the placebo group. Cognitive assessment data from the SIB scale showed that memantine significantly reduces cognitive decline in patients relative to placebo-treated patients.³¹ Using the ADCS-ADL-19 scale for functional assessment of daily living, memantine was found to significantly reduce functional deterioration in patients compared to the placebo group.Results from the CIBIC-Plus also showed that memantine significantly reduced global deterioration in patients compared to the placebo study arm.Adverse event and safety data for the memantine group showed less agitation and fewer urinary tract infections.      

Tariot and colleagues³² conducted a 24-week multicenter, randomized, double-blind, placebo-controlled trial in 403 subjects with moderate-to-severe Alzheimer’s disease (MMSE range, 5-14) on combination therapy with the ChEI donepezil. All subjects received donepezil for at least 6 months, and 3 months on a stable dose. All patients taking donepezil were then randomized to receive either adjunctive memantine 20 mg per day or placebo. Principal efficacy measures were the SIB, ADCS-ADL-19, and CIBIC-Plus. Completion rates were 85% in the combination donepezil-plus-memantine group and 75% in the donepezil-alone group. SIB results showed patients in the combination therapy group improved over their baseline during the 6-month period, compared to initial stabilization followed by modest decline in the donepezil-alone group. Similar data were seen on the activities of daily living scale. Both groups declined modestly, and the decline in the donepezil group was greater than in the combination group. The CIBIC-Plus scale showed more improvement in the memantine-plus-donepezil group compared to the donepezil-alone group. The side-effect profile shows less agitation in the combination group compared to donepezil alone. There were some increased cases of confusion in the combination group, but they were transient.