Memantine

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 06.04.2021
Released 12.02.2003
Expires For CME 06.04.2024

Memantine

Author: K K Jain MD†

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Memantine

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Introduction

Historical note and terminology

Memantine hydrochloride was originally synthesized in 1963 at Eli Lilly & Co as an antidiabetic agent but was found to be ineffective in lowering elevated blood sugar. Merz & Co in Germany took it over and, a decade later, showed its effectiveness in Parkinson disease. In 1989, therapeutic action of memantine was shown to be due to antagonism of N-methyl-D-aspartate receptors (11), and it was launched in Germany for the treatment of dementia. Further clinical trials were conducted on its use in Alzheimer disease between 1995 and 2000, and the drug was approved in the European Union in 2002. The FDA approved it for the treatment of moderate to severe Alzheimer disease in 2003. It is marketed in the United States under the trade name of “Namenda” (Forest Laboratories).

Pharmacology

The chemical name of memantine hydrochloride is 1-amino-3,5-dimethyl-adamantine hydrochloride.

Memantine hydrochloride (chemical structure)

(Contributed by Dr. K K Jain.)

Pharmacodynamics. Memantine is a noncompetitive and low-affinity N-methyl-D-aspartate antagonist, with a high voltage dependency and fast receptor kinetics, but none of the undesirable effects associated with the classical compounds of this category. Rationale for its use is based on the hypothesis that persistent activation of N-methyl-D-aspartate receptors in the brain by glutamate contributes to neurodegeneration and symptoms of Alzheimer disease. Memantine is a neuroprotective agent.

Mechanisms of action of memantine are:

	• Memantine and Mg2+ occupy the same N-methyl-D-aspartate receptor channel and are mutually exclusive.
	• Unlike Mg2+, memantine does not leave the channel so easily.
	• Block of N-methyl-D-aspartate receptor channels is partial and 15% to 20% of the channels unblock in the absence of an agonist and are available for subsequent physiological activation.
	• Increases brain-derived neurotrophic factor levels in the limbic cortex.
	• Antagonist of activity at the serotonergic type 3 (5-HT3) and nicotinic acetylcholine receptors.

Pharmacokinetics. Memantine is absorbed completely from the gastrointestinal tract, and peak plasma concentrations are achieved in 6 to 8 hours after oral intake. By repeated administration, a steady-state plasma level is reached in 21 days. Under therapeutic conditions in man, the serum levels of memantine with daily maintenance doses of 20 mg range from 0.5 to 1.0 mM. The plasma clearance half-life is 60 to 100 hours. The protein binding is 42% to 45%. The elimination of memantine is mainly by kidneys as unchanged substance as well as its hydroxylated metabolites. Memantine crosses the blood-brain barrier but cerebrospinal fluid level is 20% to 50% lower due to albumin binding in serum.

Therapeutic drug monitoring. A high-performance liquid chromatography with ultraviolet assay for memantine in serum from demented patients has been developed and validated (07). It can be used as a daily routine for analysis of serum samples of patients. Measurements of memantine concentrations suggest that therapeutic levels may only be reached by high doses of memantine.

Clinical trials

The M-Best Study (Benefit and Efficacy in Severely demented patients during treatment with memantine) was a double-blind, placebo-controlled, phase III trial of memantine conducted in Sweden on care-dependent patients with severe dementia (25). The trial population consisted of 161 patients, 51% with vascular dementia and 49% with Alzheimer disease. Treated patients were given 10 mg memantine per day for 12 weeks, and evaluation was done using Clinical Global Impression of Change by the physician and Behavioral Rating Scale for Geriatric Patients by the nursing staff. The results supported the hypothesis that memantine treatment leads to functional improvement and reduces care dependence in severely demented patients.

Another study conducted in Germany assessed the efficacy of memantine in the first large-scale systematic and prospective clinical trial of therapeutic intervention in advanced stages of dementia (19). A group of 531 advanced dementia patients, separated by severity according to Global Dementia Scale stages, determined the drug's efficacy on 2 independent levels by assessing physicians' Clinical Global Impression of Change rating at the end of the 6-week observation period and by the elementary ADL (activities of daily living) function levels given by caregivers using the D-Scale-of-Change. Improvement was noted by both caregivers and physicians.

A United States trial of memantine in 2003 involved 32 sites across the country and 252 patients diagnosed with advanced Alzheimer disease. This randomized, 6-month, placebo-controlled, double-blind, multicenter trial was aimed at functional improvement of patients with moderate to severe Alzheimer disease. Several validated scales were used to measure changes in cognition, function, and global performance, including the Severe Impairment Battery, ADL Inventory, and Clinician's Interview-Based Impression of Change. At the end of the study, patients receiving placebo scored more than 40% below patients taking memantine on standard assessment scales.

In a reassessment of 13 randomized controlled trials of Alzheimer disease that were published prior to the end of 2013, memantine therapy showed significant benefits in terms of cognition, mental state, activities of daily life, and the clinician's global impression without significant serious adverse events, although it did increase the risk for somnolence (10).

A systematic analysis of data from double-blind, parallel group, placebo-controlled, randomized trials of memantine in persons with dementia of different etiologies and severities of Alzheimer disease with agitation showed a small clinical benefit of memantine in moderate-to-severe Alzheimer disease but no benefit in those with mild form of the disease (15).

Indications

Memantine hydrochloride is indicated for the treatment of moderate to severe dementia of Alzheimer type.

Off-label uses

	• Because disturbed glutamate neurotransmission may be central to the pathophysiology of such conditions as obesity, schizophrenia, depression, substance abuse, pain disorders, and glaucoma, clinical trials have explored the role of memantine in these and other disorders.
	• Wernicke-Korsakoff syndrome.
	• Huntington disease.
	• Bipolar disorder. A case report and review of literature indicate that memantine may be an effective and safe method of augmentation of mood stabilizing therapy in bipolar depression (12).
	• Memantine has been used for the treatment of vascular dementia.
	• Use of memantine in Alzheimer dementia developing in Down syndrome has been suggested, but no recommendations can currently be made.
	• Memantine has been used successfully for the treatment of Huntington disease in a mouse model.
	• Mild-to-moderate dementia with Lewy bodies.
	• Memantine given for treatment of Parkinson disease dementia has been reported to improve levodopa-induced dyskinesia and on-off phenomena (22).
	• Memantine was ineffective a multicenter, randomized, double-blind, placebo-controlled trial on patients with frontotemporal dementia (03).
	• Prevention of cognitive decline in patients receiving whole-brain radiotherapy (04).
	• A randomized, double-blind, placebo-controlled trial of memantine for fragile X-associated tremor/ataxia syndrome showed no benefit (21).
	• A double-blind, randomized controlled trial of memantine in fibromyalgia showed that increase of cerebral metabolites as biomarkers determined by magnetic resonance spectroscopy confirmed the efficacy of treatment (06).
	• Memantine has been used as monotherapy or adjunctive therapy for prophylaxis of refractory chronic migraine headaches (09).
	• A double-blind controlled clinical trial showed that memantine is an effective adjuvant agent for reducing obsessive compulsive symptoms in patients with bipolar disorder (20).
	A meta-analysis of 8 studies has shown that memantine is effective and well tolerated as add-on to first-line therapy for patients with severe obsessive-compulsive disorder refractory to serotonin reuptake inhibitor monotherapy (16).
	• A double-blind, placebo-controlled clinical trial showed that memantine as adjunctive to antipsychotic regimen improved verbal memory, learning, verbal letter fluency, and working memory without improvement of psychotic symptoms in individuals with chronic schizophrenia (08).
	• A systematic review and meta-analysis showed that memantine may have the potential to decrease pain, but it can also increase common adverse effects (13). No clear recommendations can be made about its routine clinical use for chronic pain until larger and more definitive studies are conducted.
	• Memantine has been shown to provide neuroprotection and lead to neuroplasticity in the poststroke stage in preclinical stroke models, indicating its potential to improve functional recovery in human stroke patients (14).

References

01: Atri A, Shaughnessy LW, Locascio JJ, Growdon JH. Long-term course and effectiveness of combination therapy in Alzheimer disease. Alzheimer Dis Assoc Disord 2008;22(3):209-21. PMID 18580597
02: Borges LG, Bonakdarpour B. Memantine-induced chorea and dystonia. Pract Neurol 2017;17(2):133-4. PMID 27927775
03: Boxer AL, Knopman DS, Kaufer DI, et al. Memantine in patients with frontotemporal lobar degeneration: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2013;12(2):149-56. PMID 23290598
04: Brown PD, Pugh S, Laack NN, et al. Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial. Neuro Oncol 2013;15(10):1429-37. PMID 23956241
05: Chen R, Chan PT, Chu H, et al. Treatment effects between monotherapy of donepezil versus combination with memantine for Alzheimer disease: a meta-analysis. PLoS One 2017;12(8):e0183586. PMID 28827830
06: Fayed N, Olivan-Blázquez B, Herrera-Mercadal P, et al. Changes in metabolites after treatment with memantine in fibromyalgia. A double-blind randomized controlled trial with magnetic resonance spectroscopy with a 6-month follow-up. CNS Neurosci Ther 2014;20(11):999-1007. PMID 25230216
07: Haen E, Koeber R, Klünemann HH, et al. Implementation of a cost-effective HPLC/UV approach for routine medical quantification of memantine in human serum. Ther Drug Monit 2012;34(6):702-12. PMID 23007745
08: Hassanpour F, Zarghami M, Mouodi S, et al. Adjunctive memantine treatment of schizophrenia: a double-blind, randomized placebo-controlled study. J Clin Psychopharmacol 2019;39(6):634-8. PMID 31688396
09: Huang L, Bocek M, Jordan JK, Sheehan AH. Memantine for the prevention of primary headache disorders. Ann Pharmacother 2014;48(11):1507-11. PMID 25159002
10: Jiang J, Jiang H. Efficacy and adverse effects of memantine treatment for Alzheimer's disease from randomized controlled trials. Neurol Sci 2015;36(9):1633-41. PMID 25899425
11: Kornhuber J, Bormann J, Retz W, Hubers M, Riederer P. Memantine displaces [3H]MK-801 at therapeutic concentrations in postmortem human frontal cortex. Eur J Pharmacol 1989;166(3):589-90. PMID 2680528
12: Krzystanek M, Surma S, Pałasz A, Romańczyk M, Krysta K. Possible antidepressant effects of memantine-systematic review with a case study. Pharmaceuticals (Basel) 2021;14(5):481. PMID 34070216
13: Kurian R, Raza K, Shanthanna H. A systematic review and meta-analysis of memantine for the prevention or treatment of chronic pain. Eur J Pain 2019;23(7):1234-50. PMID 30848504
14: MartInez-Coria H, Arrieta-Cruz I, Cruz ME, López-Valdés HE. Physiopathology of ischemic stroke and its modulation using memantine: evidence from preclinical stroke. Neural Regen Res 2021;16(3):433-9. PMID 32985462
15: McShane R, Westby MJ, Roberts E, et al. Memantine for dementia. Cochrane Database Syst Rev 2019;3:CD003154.** PMID 30891742
16: Modarresi A, Chaibakhsh S, Koulaeinejad N, Koupaei SR. A systematic review and meta-analysis: memantine augmentation in moderate to severe obsessive-compulsive disorder. Psychiatry Res 2019;282:112602. PMID 31630042
17: Moritoyo T, Hasunuma T, Harada K, et al. Effect of renal impairment on the pharmacokinetics of memantine. J Pharmacol Sci 2012;119(4):324-9. PMID 22863669
18: Riordan KC, Hoffman Snyder CR, Wellik KE, Caselli RJ, Wingerchuk DM, Demaerschalk BM. Effectiveness of adding memantine to an Alzheimer dementia treatment regimen which already includes stable donepezil therapy: a critically appraised topic. Neurologist 2011;17(2):121-3. PMID 21364371
19: Ruther E, Glaser A, Bleich S, Degner D, Wiltfang J. A prospective PMS study to validate the sensitivity for change of the D-scale in advanced stages of dementia using the NMDA-antagonist memantine. Pharmacopsychiatry 2000;33(3):103-8. PMID 10855461
20: Sahraian A, Jahromi LR, Ghanizadeh A, Mowla A. Memantine as an adjuvant treatment for obsessive compulsive symptoms in manic phase of bipolar disorder: a randomized, double-blind, placebo-controlled clinical trial. J Clin Psychopharmacol 2017;37(2):246-9. PMID 28099183
21: Seritan AL, Nguyen DV, Mu Y, et al. Memantine for fragile X-associated tremor/ataxia syndrome: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2014;75(3):264-71. PMID 24345444
22: Vidal EI, Fukushima FB, Valle AP, Villas Boas PJ. Unexpected improvement in levodopa-induced dyskinesia and on-off phenomena after introduction of memantine for treatment of Parkinson's disease dementia. J Am Geriatr Soc 2013;61(1):170-2. PMID 23311565
23: Wei H, Zhu X, Li Y. Application value of serum biomarkers for choosing memantine therapy for moderate AD. J Neurol 2018;265(8):1844-9. PMID 29948244
24: Wilkinson D. A review of the effects of memantine on clinical progression in Alzheimer's disease. Int J Geriatr Psychiatry 2012;27(8):769-76. PMID 21964871
25: Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-best study (Benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry 1999;14(2):135-46. PMID 10885864

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Memantine

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Memantine

Memantine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Metal neurotoxicity

Vascular cognitive impairment

Addictive disorders

Automatic-voluntary dissociation

Wilson disease

Serotonin syndrome

Pre-mild cognitive impairment

PART (Primary age-related tauopathy)

Memantine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

Media

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Metal neurotoxicity

Vascular cognitive impairment

Addictive disorders

Automatic-voluntary dissociation

Wilson disease

Serotonin syndrome

Pre-mild cognitive impairment

PART (Primary age-related tauopathy)

This is an article preview.
Start a Free Account
to access the full version.