Rationale for Combining Glutamatergic and Cholinergic Approaches in the Symptomatic Treatment of Alzheimer's Disease

Paul T Francis; Chris G Parsons; Roy W Jones

Expert Rev Neurother. 2012;12(11):1351-1365.

Abstract

A total of 40 years of biochemical, clinical and neuropathological research have revolutionized our understanding of the pathophysiology of Alzheimer's disease, yet at the present moment the only drugs licensed for treatment are targeted essentially at symptoms. Some disease-modifying drugs remain in clinical trials, but many that have used similar approaches have failed. It is therefore of considerable interest to examine the optimal way of using existing medications for the benefit of patients. This article looks at the rationale behind the combined use of acetylcholinesterase inhibitors and the N-methyl-D-aspartate-receptor antagonist, memantine, from both preclinical and clinical perspectives.

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Table 1. Cholinergic drugs in clinical development/marketplace.
Drug	Receptor activity	Phase	Key results of clinical trials	Approval date and indication
Donepezil	Reversible, noncompetitive, selective AChEI⁴³	IV (marketed)¹²³	Positive effect on global status, cognition, function and behavior; gastrointestinal side effects¹²⁴	1997; all AD stages (mild to moderately severe AD in Europe)^43,125
Rivastigmine	Pseudo-irreversible AChEI and BChEI⁴⁴	IV (marketed)¹²³	Positive effect on global status, cognition and function in mild-to-moderate AD; gastrointestinal side effects¹²⁶	1998; mild to moderately severe AD⁴⁴
Galantamine	Reversible, competitive, selective AChEI; nicotinic-receptor allosteric modulator⁴⁵	IV (marketed)¹²³	Positive effect on cognition in mild-to-moderate AD; possible positive effect on function and behavior; gastrointestinal side effects¹²⁷	2000; mild to moderately severe AD⁴⁵
Tacrine	Reversible AChEI and BChEI¹²⁸	(Marketed; no longer recommended)¹²⁸	Considerable side effects, including hepatotoxicity¹²⁸	1993; mild to moderately severe AD
Phenserine	AChEI¹²³	III (discontinued)¹²³	Possible positive effect on cognition; nonsignificant¹²³
Huperzine A	Reversible, competitive, selective AChEI^129,130	II/III^{123,129,130,202}	Possible positive effect on global status, cognition (memory) and function; insufficient evidence^128–131	1994; AD (China only)¹³⁰
Ispronicline (AZD-3480)	Selective nicotinic α4β2-receptor agonist^123,132	II/III^123,132,202	Possible positive effect on cognition (memory); nonsignificant¹²³
AZD-1446	Nicotinic α4β2-receptor activator²⁰³	II²⁰²	No cognitive or global benefits in AD²⁰⁴
EVP-6124	Selective nicotinic α7-receptor agonist^123,132	II^123,132,202	Possible positive effect on cognition (nonverbal learning, memory, and executive function)^132,133
Ladostigil (TV-3326)	AChEI; BChEI¹³⁴	II²⁰²	Reverses memory deficits in animals^134,202
ST101 (ZSET1446)	Potentiates nicotine-induced acetylcholine release; not an AChEI¹³⁵	II²⁰²	Improves learning and memory and reverses cognitive deficits in animals^135,136,202
Varenicline	Selective nicotinic α4β2-receptor partial agonist¹³⁷	II²⁰²	No cognitive benefits in mild-to-moderate AD²⁰²
Pozanicline (ABT-089)	Nicotinic α4β2 and α6β2-receptor partial agonist¹²³	II (discontinued)^123,202	Reverses hyoscine-induced cognitive deficits in healthy volunteers; no cognitive benefits in mild-to-moderate AD¹²³
RG 3487	Selective nicotinic α7-receptor partial agonist¹³²	II (discontinued)¹³²	Improves cognitive function in mild-to-moderate AD¹³²
AF-102B	M₁ muscarinic-receptor agonist¹²³	I (discontinued)¹²³	Cognitive benefits in animals;¹³⁸undesirable side effects in humans¹²³
Talsaclidine (WAL 2014)	M₁ muscarinic-receptor agonist¹²³	I (discontinued)¹²³	Modest cognitive benefits in animals;¹³⁹ undesirable side effects in humans¹⁴⁰
Lecithin	Dietary source of choline¹⁴¹	N/A	Insufficient evidence¹⁴¹
Nicotine	Nicotinic α4β2 and α7-receptor agonist¹⁴²	N/A	Insufficient evidence¹⁴²
Physostigmine	Reversible AChEI and BChEI¹²⁸	(Discontinued)¹⁴³	Possible positive effect on cognition (memory); gastrointestinal side effects^128,143
Metrifonate	Irreversible, nonselective AChEI and BChEI¹⁴⁴	(Discontinued)¹⁴⁴	Positive effect on global status, cognition and function in mild to moderate AD; respiratory failure and death¹⁴⁴
Velnacrine	Reversible AChEI¹⁴⁵	(Discontinued)	Considerable side effects, including hepatotoxicity¹⁴⁵

AChEI: Acetylcholinesterase inhibitor; AD: Alzheimer's disease; BChEI: Butyrylcholinesterase inhibitor; N/A: Not applicable.

Table 2. Glutamatergic drugs in clinical development/marketplace.
Drug	Receptor activity	Phase	Key results of clinical trials	Approval date and indication
Memantine	Uncompetitive, voltage-dependent NMDA-receptor antagonist¹²³	IV (marketed)¹²³	Positive effect on global status, cognition and function in moderate-to-severe AD; reduces agitation development; well tolerated¹⁴⁶	2002; moderate-to-severe AD¹⁴⁷
Neramexane	Uncompetitive NMDA-receptor antagonist⁹⁸	III²⁰²	Positive effect on memory in animals⁹⁸
CX-516	AMPA-receptor positive allosteric modulator²⁰²	II²⁰²	Possible positive effect on memory and cognition¹⁴⁸
D-cycloserine	NMDA-receptor modulator¹⁴⁹	II (nondemented elderly)²⁰²	Positive effect on memory in healthy subjects;¹⁵⁰ no benefits in AD¹⁴⁹
LY451395	AMPA-receptor potentiator¹³²	II^132,202	No cognitive benefits in mild-to-moderate AD; possible behavioral benefit¹⁵¹
EVT 101	NMDA-receptor antagonist (at NR2B subunit)¹³²	I (healthy subjects) (discontinued)^132,202	Possible positive effect on brain function in healthy subjects¹³²

AD: Alzheimer's disease; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA: N-methyl-D-aspartate; NR: NMDA receptor.

Table 3. Preclinical investigations of memantine–acetylcholinesterase inhibitor combination treatment.
Study (year)	Title	Ref.
Ihalainen et al. (2011)	Effects of memantine and donepezil on cortical and hippocampal acetylcholine levels and object recognition memory in rats	[16]
Martinez-Coria et al. (2009)	Combination of memantine and donepezil reverses cognitive deficits in transgenic mice with both amyloid-β plaques and neurofibrillary tangles	[103]
Neumeister and Riepe (2012)	Synergistic effects of antidementia drugs on spatial learning and recall in the APP23 transgenic mouse model of AD	[104]
Wise and Lichtman (2007)	The uncompetitive NMDA-receptor antagonist memantine prolongs spatial memory in a rat delayed radial-arm maze memory task	[100]
Woodruff-Pak et al. (2007)	Preclinical investigation of the functional effects of memantine and memantine combined with galantamine or donepezil	[101]
Yamada et al. (2005)	Effects of memantine and donepezil on amyloid β-induced memory impairment in a delayed-matching to position task in rats	[102]

APP: Amyloid precursor protein; NMDA: N-methyl-D-aspartate; NR: NMDA receptor.

Table 4. Mixed cholinergic and glutamatergic drugs in clinical development/market place.
Drug	Receptor activity	Phase	Key results of clinical trials
Latrepirdine (dimebon)	Weak AChEI and BChEI; glutamate-receptor modulator; mitochondrial modulation¹⁵²	III^132,202 (discontinued)²⁰⁵	Insufficient evidence from Phase III (despite positive Phase II findings)¹⁵²
Nefiracetam	Nicotinic-receptor potentiator; NMDA-receptor potentiator; modulates the glycine binding site of the NMDA receptor¹⁵³	II²⁰²	Possible positive effect on cognitive function²⁰²
Piracetam	α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor allosteric modulator;¹⁵⁴ muscarinic cholinergic activity¹⁵⁵	NA	Insufficient evidence¹⁵⁵

AD: Alzheimer's disease; AChEI: Acetylcholinesterase inhibitor; BChEI: Butyrylcholinesterase inhibitor; NA: Not applicable.

Table 5. Studies examining the efficacy of memantine–acetylcholinesterase inhibitor combination treatment in patients with Alzheimer's disease/dementia.
Study (year)	Title	Publication	Ref.
*Prospective clinical studies*
Tariot et al. (2004)	Memantine treatment in patients with moderate to severe AD already receiving donepezil. A randomized controlled trial	JAMA 291(3), 317–324 (2004)	[79]
Porsteinsson et al. (2008)	Memantine treatment in patients with mild to moderate AD already receiving a cholinesterase inhibitor: a randomized, double-blind, placebo-controlled trial	Curr. Alzheimer Res. 5(1), 83–89 (2008)	[109]
Choi et al. (2011)	Tolerability and efficacy of memantine add-on therapy to rivastigmine transdermal patches in mild to moderate AD: a multicenter, randomized, open-label, parallel-group study	Curr. Med. Res. Opin. 27(7), 1375–1383 (2011)	[116]
Dantoine et al. (2006)	Rivastigmine monotherapy and combination therapy with memantine in patients with moderately severe AD who failed to benefit from previous cholinesterase inhibitor treatment	Int. J. Clin. Pract. 60(1), 110–118 (2006)	[156]
Howard et al. (2012)	Donepezil and memantine for moderate-to-severe AD	N. Engl. J. Med. 366, 893–903 (2012)	[119]
Olin et al. (2010)	Safety and tolerability of rivastigmine capsule with memantine in patients with probable AD: a 26-week, open-label, prospective trial (study ENA713B US32)	Int. J. Geriatr. Psychiatry 25(4), 419–426 (2010)	[157]
Riepe et al. (2007)	Domain-specific improvement of cognition on memantine in patients with AD treated with rivastigmine	Dement. Geriatr. Cogn. Disord. 23(5), 301–306 (2007)	[158]
*Post hoc analyses*
Cummings et al. (2006)	Behavioral effects of memantine in AD patients receiving donepezil treatment	Neurology 67(1), 57–63 (2006)	[83]
Farlow et al. (2010)	A 25-week, open-label trial investigating rivastigmine transdermal patches with concomitant memantine in mild-to-moderate AD: a post hoc analysis	Curr. Med. Res. Opin. 26(2), 263–269 (2010)	[117]
Feldman et al. (2006)	Activities of daily living in moderate-to-severe AD: an analysis of the treatment effects of memantine in patients receiving stable donepezil treatment	Alzheimer Dis. Assoc. Disord. 20(4), 263–268 (2006)	[112]
Schmitt et al. (2006)	Cognitive response to memantine in moderate to severe AD patients already receiving donepezil: an exploratory reanalysis	Alzheimer Dis. Assoc. Disord. 20(4), 255–262 (2006)	[113]
van Dyck et al. (2006)	A responder analysis of memantine treatment in patients with AD maintained on donepezil	Am. J. Geriatr. Psychiatry 14(5), 428–437 (2006)	[114]
Winblad et al. (2006)	Memantine in moderate-to-severe AD: a meta-analysis of randomized clinical trials	Dement. Geriatr. Cogn. Disord. 24, 20–27 (2007)	[80]
*Observational & long-term studies*
Atri et al. (2008)	Long-term course and effectiveness of combination therapy in AD	Alzheimer Dis. Assoc. Disord. 22, 209–221 (2008)	[120]
Lopez et al. (2009)	Long-term effects of the concomitant use of memantine with cholinesterase inhibition in AD	J. Neurol. Neurosurg. Psychiatry 80(6), 600–607 (2009)	[121]
Schneider et al. (2011)	Treatment with cholinesterase inhibitors and memantine of patients in the AD Neuroimaging Initiative	Arch. Neurol. 68(1), 58–66 (2011)	[118]