Memantine

Memantine is a drug used to treat moderate to severe Alzheimer's disease. It was the first drug to be approved by the Food and Drug Administration for this purpose. By changing the activity of NMDA receptors in the brain, it can improve thinking and daily activities of patients with the disease. Side effects are generally mild and do not restrict treatment.

Memantine has the brand name Namenda, and it is marketed in the United States by Forest Pharmaceuticals. Memantine has several other brand names, including Memox, Akatinol, Abixa (in Canada), and Axura. Memantine was approved for use in Europe in 2002 and in the US in 2003.

Uses/Indications

Memantine is used to treat moderate to severe Alzheimer’s disease. The evidence that it can be used to treat milder forms of the disease has not been convincing. Memantine is being investigated as a treatment for other neurological disorders such as dementia associated with HIV/AIDS, drug dependence, depression, and obsessive-compulsive disorder.

How Memantine Is Taken

Memantine is available as 5 mg or 10 mg tablets and in an oral suspension of 2 mg memantine in 1 ml of solution. Typically, dosage starts at 5 mg daily for one week. The dose is increased by 5 mg every week until the target of daily 20 mg is reached.

How Memantine Works

The progression of Alzheimer’s disease is thought to involve overactivation of NMDA receptors in the brain. This overactivation can kill brain cells, called neurons, by flooding the cell with calcium. Memantine blocks the NMDA receptor, changes its activity, and prevents overactivation. Other receptors in the brain bind memantine, but whether this binding contributes to the effectiveness of memantine is not known.

How the Body Affects Memantine

The majority of memantine is excreted unchanged in the urine. A minor portion is metabolized (broken down) in the liver. Thus, almost all of a dose of memantine enters the circulation. Concentrations of memantine in the blood reach a peak 3-7 hours after taking a dose. The concentration of memantine in the blood is reduced by half (half-life) in 60-80 hours.

Kidney cells require energy to secrete memantine into the urine. The pH (a measure of acidity) of the urine determines how much memantine is excreted. If the urine is alkaline (high pH) more memantine is re-absorbed into the body.

In special populations

Because memantine is largely excreted from the body in the urine, kidney function affects memantine elimination. ^[1] The average concentration of memantine in the blood increases 60% in individuals with moderate kidney impairment, and it increases 115% in individuals with severe kidney impairment. The target dosage should be reduced in individuals with severely impaired kidney function.

Side Effects

Side effects during treatment with memantine are mild and include the following:

• Dizziness
• Headache
• Confusion
• Constipation

Overdose

Overdose is unlikely to cause serious adverse reactions. An overdose of 400 mg memantine has been reported.^[2] The patient experienced hallucinations, restlessness, a hypnotic state, and loss of consciousness. The patient recovered without further complication.

Risks and Precautions

Severe kidney problems can reduce excretion of memantine and increase levels in the blood. In this situation, a lower target dose may be used. Memantine excretion is also reduced by alkaline urine. Some medications or infections in the urinary tract can increase the alkalinity of the urine.

Drug Interactions

Memantine interacts with other drugs that are excreted by the kidneys. A woman became delirious and experienced muscle contractions that prevented her from walking when memantine was added to her trimethoprim therapy.^[3] hydrochlorothiazide, cimetidine (Tagamet), and nicotine, among several other drugs, are primarily excreted in the urine and may reduce the excretion of Namenda. Drugs that change the pH of the urine can also influence the excretion of memantine. Some drugs that change urine pH include the carbonic anhydrase inhibitors (e.g., acetazolamide (Diamox)) and sodium bicarbonate.

Memantine may interact with other drugs that bind to the NMDA receptor, such as amantadine (Symmetrel), ketamine (Ketalar), and dextromethorphan.

Clinical Trials

Memantine may improve thinking, daily activities, and mood of patients with moderate to severe Alzheimer’s disease. No evidence exists, however, that it actually slows the progression of cell death that is associated with the disease. Clinical trials that test the effectiveness of memantine use surveys and questionnaires that score improvements using numbers. This method of assessment has been criticized because an improvement in scores on a survey do not necessarily mean the patient will show improved mental and physical function. Indeed, often the scores only improve slightly and no change may be seen in the patient.

The New England Journal of Medicine published a study suggesting that treatment with memantine (20 mg daily) for 28 weeks improves the symptoms of Alzheimer’s disease ^[4] On a scale measuring the caregivers’ and clinicians’ impression of improvement, memantine improved scores by 0.3 over placebo. Scores of daily living improved by 2.1 over placebo, and significant improvements in thinking ability were seen. Almost 30% of patients receiving memantine and 10% of patients receiving placebo were considered to respond to treatment. Another study with daily 10 mg memantine treatment for 12 weeks found that Physician-assessed improvements were seen in 73% of memantine-treated and 45% of placebo-treated patients.^[5] A score measuring care-dependence improved by 2 points in patients receiving memantine. An analysis of six studies found that 18% of memantine-treated and 28% of placebo-treated patients had worsening of symptoms.^[6] Severe worsening of symptoms was seen in 11% of memantine-treated and 21% of placebo-treated patients.

Other studies are less convincing. A 24-week study found that memantine did not improve measures of daily living but did slightly improve measures of thinking ability. ^[7] An analysis of six clinical trials showed that memantine improved behavioral and psychological symptoms of dementia by 2 points.^[8] This is a small change, and the authors questioned whether it was significant enough to see any improvements in the patients.

References

1. ↑ Periclou A, Ventura D, Rao N, Abramowitz W. Pharmacokinetic study of memantine in healthy and renally impaired subjects. Clin Pharmacol Ther. 2006 Jan;79(1):134-43. PMID 16413248
2. ↑ Forest Pharmaceuticals. Memantine Product Information. PDF.</ PDF
3. ↑ Moellentin D, Picone C, Leadbetter E. Memantine-induced myoclonus and delirium exacerbated by trimethoprim (March). Ann Pharmacother. 2008 Mar;42(3):443-7. PMID 18303133
4. ↑ Reisberg B, Doody R, Stöffler A, et al. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348:1333-41.
5. ↑ 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). Abstract. Int J Geriatr Psychiatry 1999;14:135-46.
6. ↑ Wilkinson D, Andersen HF. Analysis of the effect of memantine in reducing the worsening of clinical symptoms in patients with moderate to severe Alzheimer's disease. Abstract. Dement Geriatr Cogn Disord 2007;24:138-45.
7. ↑ van Dyck CH, Tariot PN, Meyers B, et al. A 24-week randomized, controlled trial of memantine in patients with moderate-to-severe Alzheimer disease. Abstract. Alzheimer Dis Assoc Disord 2007;21:136-43.
8. ↑ Maidment ID, Fox CG, Boustani M, et al. Efficacy of memantine on behavioral and psychological symptoms related to dementia: a systematic meta-analysis. Abstract. Ann Pharmacother 2008;42:32-8.

External Links

• Alzheimer’s Society of Canada: Main Page
• Drugs.com: Memantine Drug Interactions
• Forest Pharmaceuticals: Namenda Main Page
• Food and Drug Administration: Namenda; Memantine Hydrochloride Tablets/Oral Suspension Product Information