Background

Memantine is marketed for the treatment of moderate to severe Alzheimer's disease in the United States, Canada, Europe, China, and other countries, and for the treatment of dementia in Germany, where it has been on the market since 1989 under the name Akatinol. Memantine received European marketing approval in 2002 and U.S. FDA approval in 2003. It is available as immediate-release tablets, solution, or extended-release capsules. Generic versions are expected to become available in 2015, when Merz Pharmaceuticals's patent to this drug expires. Memantine's side effects include fatigue, increases in blood pressure, dizziness, headache, constipation, confusion, and sleepiness, among others.

Memantine is the only FDA-approved drug for the treatment of Alzheimer's disease that is not an acetyl cholinesterase inhibitor. The drug is a noncompetitive, low- to medium-affinity antagonist of NMDA glutamate receptors in the brain. Memantine's principal mechanism of action is believed to be the blockade of current flow through channels of NMDA receptor-operated ion channels, reducing  the effects of excitotoxic glutamate release. Memantine has higher affinity than Mg2⁺ ions at the NMDA receptor, thereby blocking prolonged Ca2⁺ influx while preserving transient physiological activation of the ion channels by activity-dependent, synaptically released glutamate. Memantine also is an antagonist of the type 3 serotonergic (5-HT3) receptor, and a low-affinity antagonist of the nicotinic acetylcholine receptor, but does not bind other receptors of neurologic or psychiatric drugs, such as adrenergic, benzodiazepine, dopamine, GABA receptors, or voltage-dependent calcium, sodium, or potassium channels.

Findings

In moderate to severe Alzheimer’s disease, a pooled analysis of six trials found that memantine helped treat and prevent behavioral symptoms of AD. Given at 20 mg/day, memantine treatment improved delusion, hallucinations, agitation, aggression, and irritability as measured by the Neuropsychiatric Inventory (NPI). In patients without these symptoms at baseline, memantine reduced their emergence. A meta-analysis of 1,826 patients in six trials reached the same conclusion (Gauthier et al., 2008; Winblad et al., 2007). Memantine's effect size is small.

In a 28-week, Phase 3 trial of 252 patients with moderate to severe AD, memantine modestly improved attention, global well-being, daily function, and independence. This was measured by the CIBIC, ADCS-ADL, and the Severe Impairment Battery (SIB); examples of functions measured by this scale include following conversations and performing light household chores such as clearing the table. NPI scores for agitation and delusion also improved on memantine, as did behavioral symptoms. The investigators concluded that memantine slows the clinical deterioration at this stage of AD. The open-label extension phase of this study enrolled 175 patients; it showed that a meaningful clinical benefit lasted for a year. Patients who switched to memantine from the blinded study's placebo arm improved on cognitive, functional, and global measures compared with their projected rate of continued decline (see Apr 2003 story on Reisberg et al., 2003; see Jan 2006 story on Reisberg et al., 2006).

Trials of memantine in mild to moderate AD yielded mixed results. Two six-month, Phase 3 studies in patients with mild to moderate AD showed modest treatment benefits for memantine over placebo. One study, conducted in 403 patients in the United States, showed a benefit for memantine over placebo on both the ADAS-cog scale and the CIBIC-plus global outcome. The other trial, conducted in 470 patients in Europe, showed benefits of memantine only at interim time points, and fell short of statistical significance at study completion. In 2004 Forest Laboratories filed for FDA approval of memantine as a treatment for mild AD, but in 2005 the agency issued a non-approvable letter, requiring a confirmatory study. The drug was never formally approved for the early stages of AD, but is frequently prescribed at this stage. Whether memantine is clinically useful in mild AD is controversial, as meta-analyses have reported conflicting conclusions (Doody et al., 2007; Schneider et al., 2011; see also news story and commentary).

Memantine was studied in combination therapy with the cholinesterase inhibitor donepezil. The first U.S. study assessing both drugs for moderate to severe AD, a six-month, 404-patient trial, showed that memantine treatment augmented the cognitive, functional, and behavioral benefits in patients already receiving donepezil. This is the first combination drug trial for AD to yield positive results (Tariot et al., 2004; Jan 2004 news story).

Pharmacoeconomic studies have been largely positive.  The U.K.'s National Health Service reported that memantine is more cost-effective than no drug treatment in patients with moderate to severe AD. Other authors reported that memantine treatment reduced caregiver time and other societal costs, as did combination memantine-cholesterol inhibitor treatment. A systematic literature review found memantine and/or cholinesterase inhibitor treatment to be either cost-effective or cost-saving (Jones et al., 2004; Hunt, 2003; Pfeil et al. 2012, Pouryamout et al., 2012).

Memantine has been prescribed off-label for frontotemporal dementia, and an open-label trial had suggested a possible benefit for the disease's psychiatric aspects. However, in a subsequent randomized controlled trial of 20 mg memantine daily in 81 patients, the drug had no benefit on neuropsychiatric symptoms while worsening cognition in some patients (Boxer et al., 2013).

Memantine is being studied for AIDS-related dementia and cognitive dysfunction in the absence of dementia (NCT01261741), as well as autistic disorder, Asperger syndrome, and pervasive child development disorder not otherwise specified (PDD-NOS) (e.g., NCT01592786, NCT01592747, NCT01592773).

In the past, memantine has been evaluated for a range of conditions other than Alzheimer’s or dementia. Two Phase 3 studies tested this drug in more than 2,000 patients with glaucoma, but the results reportedly fell short of being able to support a marketing application for this disease (see clinicaltrials.gov, Glaucoma Research Foundation release). Memantine was studied unsuccessfully for neuropathic pain and diabetic neuropathy (Rogers et al., 2009, Sang et al., 2002). At least one early clinical trial of memantine in patients with vascular dementia appears to have shown cognitive improvement, but no further studies on this indication have been reported in the past 10 years (Wilcock et al, 2002). Trials of memantine in adults with Down's syndrome were negative (see Jan 2012 news story on Hanney et al., 2012).

For a listing of clinical trials of memantine, see clinicaltrials.gov.