Akatinol Memantine, 90 pcs., 10 mg, film-coated tablets

5 mg tablet 10 mg tablet 7-14-21-28 mg cap,sprinkle,ER 24hr dose pack 2 mg/mL solution

Trade names in Russia

Akatinol Memantine, Noodzheron, Maruxa, Memantinol, Memantal, Memantine, Memantine Canon, Memaneurin, Memantine-Richter, Memantine hydrochloride, Memikar, Alzeim, Memantine-TL

Release form

• Tablets: 10 mg, 20 mg
• Oral drops 10 mg/ml
• Oral dispersible tablets: 10 mg, 20 mg

Indications

◊ Recommendations of the Russian Ministry of Health

F00.0 Dementia in early onset Alzheimer's disease

F00.1 Late-onset dementia in Alzheimer's disease

F00.2 Dementia in Alzheimer's disease, atypical or mixed type

F00.9 Dementia in Alzheimer's disease, unspecified

◊ FDA recommendations

G.30 Alzheimer's disease

◊ EMA recommendations

G.30 Alzheimer's disease

◊ Using Off-label

• Vascular dementia
• Dementia with Lewy bodies
• Frontotemporal dementia
• HIV-associated dementia
• Multiple sclerosis

Mechanism of action and pharmacokinetics

Memantine acts as a non-competitive antagonist of NMDA receptors, preferentially binding to cation channels gated by NMDA receptors. Long-term increases in glutamate levels in the brains of patients with dementia counteract the voltage-gated block of NMDA receptors by Mg2+ ions and promote a continuous influx of Ca2+ ions into cells, which ultimately leads to neuronal degeneration. Studies show that memantine binds to NMDA receptors more effectively than Mg2+ ions, and thereby effectively blocks the long-term influx of Ca2+ ions through the NMDA channel, maintaining transient physiological activation of the channels with higher concentrations of glutamate released into the synapses. Thus, memantine protects against chronically elevated glutamate concentrations. Memantine also exhibits serotonin (5-HT3) receptor antagonistic activity with potential similar to that of the NMDA receptor, and reduced nicotinic acetylcholine receptor antagonistic activity. This drug does not bind to γ-aminobutyric acid (GABA), benzodiazepine, dopamine, adrenergic, histamine, glycine, or voltage-gated calcium, sodium, or potassium receptors.

• Little metabolized;
• It is excreted almost unchanged in the urine;
• The half-life is approximately 60-100 hours; peak plasma concentrations after 3-7 hours [3].
• Minimal inhibition of CYP450 enzymes.

Memantine (a glutamate antagonist) is one of the first drugs to act on the glutamatergic system through antagonistic interaction with ionotropic voltage-dependent glutamate receptors that selectively bind N-methyl-D-aspartate (NMDA) [1]. Overstimulation of glutamate is thought to cause neuronal damage through the mechanism of excitotoxicity. Excitotoxic cell damage leads to an overload of the neuron with calcium, which is involved in the processes of neurodegeneration [1, 2]. In addition, glutamate stimulates a number of postsynaptic receptors, such as NMDA, which are involved in normal memory processes, as well as in the development of dementia, including Alzheimer's disease (AD). The use of memantine, based on the results of controlled studies, was approved by the FDA in the USA in 2003, and since then memantine, alone or in combination with donepezil, galantamine and rivastigmine, has been used in AD dementia to correct cognitive functions, behavioral disorders, daily functioning and delay in time to institutional care [3]. Clinical data are supported by evidence of striatal glutamatergic hyperactivity in animal models of parkinsonism and Alzheimer's type dementia [4].

Memantine is the main commercially available treatment for dementia, which works by modulating glutamatergic neurotransmission through NMDA receptors [1, 5]. Other potential NMDA receptor modulators such as milacemide or cycloserine-D have failed in studies, while memantine has been effective in open-label and controlled studies in moderate to severe AD, including in care unit patients with dementia [6, 7]. The clinical approach using memantine for cognitive impairment in AD and parkinsonism is very important, since alternative effective strategies, such as the use of cholinesterase inhibitors (ChEIs) (rivastigmine, galantamine and donepezil) can cause serious side effects (nausea, vomiting, increased tremor, etc.) .) [1, 8, 9].

Pharmacokinetics of memantine

Memantine, which has the chemical formula C12H12N·HCl, was synthesized by K. Gerzon et al. [10]. It is believed that the drug preferentially targets the pathological state of the NMDA receptor, but leaves its normal physiological state uninhibited, allowing normal neurotransmission to occur [6]. As a result, memantine has a wide window of safety and is clinically well tolerated by patients. The drug is well adsorbed in the gastrointestinal tract and has absolute bioavailability (100%). After administration, the peak plasma level of memantine is achieved within 3-7 hours, while food intake does not have a significant effect on the rate of absorption. Memantine is primarily eliminated by renal excretion, and 57–82% of the total dose is excreted unchanged in the urine. This means that caution should be used when using memantine in patients with renal impairment.

Clinical studies of memantine

Dementia in AD

One of the earliest studies of memantine, conducted by B. Winblad and N. Poritis [7], examined the clinical efficacy and safety of the drug in patients with moderate to severe primary dementia. The presence of dementia was determined according to DSM-III-R criteria with a severity rating on the Global Deterioration Scale (GDS) and Mini-Mental State Examination (MMSE) less than 10 points. 82 patients received memantine at a dose of 10 mg/day, placebo - 84 patients. In the final analysis (“intention to treat” - intention to treat, English.

) at week 12, 151 patients were included: according to the type of cognitive impairment, Alzheimer's type of dementia was identified in 49%, vascular dementia in 49% (data from CT and the Khachinsky ischemic scale were used).
A positive response to the clinician-administered Clinical Global Impression (CGI-C) scale was observed in 73% of patients receiving memantine versus 45% of patients receiving placebo ( p
< 0.001), regardless of dementia type.
Additionally, scores on the Behavioral Rating Scale for Geriatric Patients (BGP) and the caregiver-rated subscale showed a 3.1-point improvement in the memantine group compared with an improvement of 1.1 points in the placebo group ( p
= 0.016).
Data from three 6-month placebo-controlled studies of memantine in patients with moderate to severe asthma were later published [11–13]. In 2 of these studies [11, 13], there was a small significant positive effect of memantine on cognitive function as measured by the Severe Impairment Battery (SIB) ( p
< 0.00001), activities of daily living as assessed by the Severe Impairment Battery (SIB) scale, and activities of daily living (ADL) scale. AD during the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) and behavior according to the Neuropsychiatric Inventory (NPI).

It should be noted that there is significant heterogeneity between studies regarding the effect on cognitive status [14]. Overall, the results obtained confirm the fact that taking memantine at a dose of 20 mg/day has a positive effect on cognitive function, mood, behavior and the ability to perform daily activities in patients with moderate to severe asthma [15]. For mild and moderate AD, the data differed: the pooled results of several studies demonstrated a marginal positive effect after 6 months of therapy on cognitive function - 0.99 points on the 70-point scale for assessing cognitive function in AD (Alzheimer's Disease Assessment Scale-cognitive subscale - ADAS-Cog ) ( R

=0.01), which indicated a mild overall clinical effect (
p
=0.03) with no effect on behavior and daily activity [15].

Vascular dementia

Memantine has also been studied in the treatment of vascular dementia [16, 17]. When using memantine at a dose of 20 mg/day in patients with mild to moderate vascular dementia, a positive effect on cognitive function was noted at week 28 (1.9 points on the ADAS-Cog scale). However, when data related to the clinical impression of effect were analyzed, no significant changes could be recorded. This suggests that in patients with mild to moderate vascular dementia, the beneficial effect of memantine on cognitive function is not clinically significant.

Combination of cholinesterase inhibitor and memantine

The combination of a cholinesterase inhibitor (ChEI) and memantine has been proposed as a potentially effective standard of care for the treatment of moderate to severe AD. Data collected from several pooled analyzes of studies have shown that combination therapy results in significant benefits in terms of cognitive function and overall clinical status compared with ChEI monotherapy [18–20]. However, the clinical efficacy of the combination, as well as the clinical significance of these data, remains controversial [3]. In June 2010, the US FDA approved memantine as a single-dose, sustained-release capsule. This drug provided a more convenient dosing regimen for memantine in patients with cognitive decline compared to the commonly available standard immediate-release memantine twice daily dose. Then in December 2014, the FDA approved a fixed-dose, sustained-release combination of memantine and donepezil for a single dose in patients with moderate to severe AD (namzariq) [21].

To evaluate the addition of memantine in patients with asthma already receiving ChEIs, 4 large randomized controlled trials were conducted: MEM-MD-02, MEM-MD-12, MEM-MD-50, DOMINO-AD [13, 22-24]. Three of them compared the standard form of memantine at a dose of 20 mg/day with placebo, and the fourth study (MEM-MD-50) compared a sustained-release form of memantine at a dose of 28 mg with placebo [25]. Evaluation of treatment outcome using the NPI scale showed a positive effect when prescribing memantine in the MEM-MD-02 and DOMINO-AD studies, as well as when prescribing a long-acting form in the MEM-MD-50 study. However, the MEM-MD-12 trial showed no significant difference between memantine (20 mg) and placebo when assessed using the NPI as an outcome measure. The ADAS-Cog and CGI-C scales were also used, which demonstrated a significant advantage of memantine over placebo in 2 of 4 studies [25].

Overall, the results of these studies and the review by W. Deardorff and G. Grossberg [25] suggest that combination therapy with memantine and donepezil for AD provides some benefits related to cognition, global clinical status and behavior compared with ChEI monotherapy . The combination drug may be convenient for patients with dysphagia, a history of poor compliance, and those with limited or insufficient care [25]. According to the National Institute of Clinical Excellence (NICE, UK), there is no high-quality evidence that fixed-combination combination therapy is significantly better than generic donepezil or memantine [3].

Long-term observational studies of memantine

In one study [26], which included 382 patients with moderate to severe asthma with a mean follow-up of 30 months and treatment duration of 22.5 months, combination therapy with memantine and ChEIs showed less deterioration in cognitive function and functional abilities compared with therapy only IHE. Another study [27] followed 943 patients with probable asthma for 62.3 months. It was shown that patients receiving memantine and ChEIs were significantly less likely to be admitted to care facilities or nursing homes compared with those receiving ChEIs alone (relative risk 0.29). However, the reliability of these data is not absolute, since variables at the start of the study, such as the severity and duration of symptoms, behavioral symptoms, and the presence of comorbidities, were not controlled.

Memantine tolerance and side effects

Overall, studies show that memantine is well tolerated by patients with AD. In a meta-analysis of controlled trials [28], memantine was associated with a higher incidence of dizziness, headaches, constipation, and somnolence compared with placebo.

While ChEI therapy was associated with an increased risk of syncope and hip fractures, memantine treatment did not increase the incidence of falls and syncope and was associated with a low incidence of fractures.

Dementia in Parkinson's disease (DKD) and diffuse Lewy body disease (DLB)

Recently, several large randomized controlled trials have been conducted on the treatment of DKD and DLB. They included both IChE and memantine as a drug. Overall, both ChEIs and memantine showed modest improvements in global CGI-C status. However, only the use of ChEIs, and not memantine, significantly improved cognitive scores on the MMSE scale [29]. Although safety results were positive for both drugs, rivastigmine showed an increased risk of side effects compared with placebo.

Several controlled and comparative studies have been conducted on memantine [30–33] (see table). They all showed that memantine had an overall positive effect on global scores in DKD and LBD. However, evidence for effects on cognition and behavioral symptoms was less convincing. L. Brennan et al. [34] published a meta-analysis that included studies of memantine that used objective tests, had a comparison group not receiving memantine, and had sufficient data to calculate effect sizes. The effect size of memantine on cognition and five individual neuropsychological functions was analyzed. In summary, the authors concluded that the small overall effect size of memantine reported in placebo-controlled studies compared with open-label studies indicates that memantine has minimal effects on cognition in DKD and LBD. However, when the studies are looked at individually, more pronounced benefits of memantine can be observed. For example, in a study by I. Litvinenko et al. [33] patients with Parkinson's disease (PD) treated with memantine showed significantly better results on MMSE scales ( p

<0.05), ADAS-Cog (
p
<0.05), Frontal Assessment Battery (FAB) (
p
<0.01) and in the clock drawing test compared with the control group at the end of the 24th week . The authors also measured homocysteine ​​levels, and patients with high homocysteine ​​levels showed significantly better results on all assessment scales when treated with memantine compared with control patients with high homocysteine ​​levels at the end of weeks 24 and 52 of the study.

Clinical trials of memantine in DKD and DLB

Overall need for NMDA receptor antagonist therapy in dementia

AD is the most common neurodegenerative disease affecting cognitive function. Dementia affects approximately 11% of people over the age of 65 years and 32% of people over the age of 85 years in the United States [35]. According to statistics, 46.8 million people worldwide had dementia in 2015, and this number is likely to double every 20 years to reach 131.5 million by 2050 [35, 36]. The social costs of dementia are enormous, and in the United States, the total cost of AD in 2010 was estimated at between US$159 and US$215 billion, excluding caregiving time and caregiving costs [36, 37].

Other dementias include “mixed dementias” and parkinsonian dementia, which also have high morbidity and mortality [38]. Treatment of B.A. and other dementias mainly consists of symptomatic therapy, since to date no drugs have been proven to convincingly prevent, slow or stop the progression of dementia. In the early stages of AD, ChEIs such as donepezil, galantamine and rivastigmine are often used, which are licensed in many countries and are available both orally and as a transdermal patch [39]. Memantine provides a novel mechanism of action through NMDA receptors and glutamatergic neurotransmitter pathways in the brain and has been extensively studied not only in AD, but also in vascular dementia and parkinsonian dementia, as well as ischemic stroke [40].

In some countries, memantine is available as a single dose and as a formulated combination with ChEIs and is an acceptable option for the treatment of moderate to severe AD dementia, for which the evidence base for memantine is sufficiently strong. Combination therapy with ChEIs and memantine is a good clinical option for use in cases where the effect of ChEIs is insufficient, but large international studies are required in the future. In patients with poor tolerance to ChEIs due to the relatively high incidence of side effects, memantine as monotherapy is an alternative because it is better tolerated.

Generics of memantine in the Russian Federation. Noogerone Research Data

The proven positive effects of memantine make this drug one of the most used for AD in the stage of moderate and severe dementia. It is used in more than 40 countries around the world, is a popular basic drug, has proven itself as an effective anti-dementia drug and is included in the list of vital and essential drugs.

In recent years, the number of companies producing memantine under different trade names has been growing in the pharmaceutical market of our country. In 2010, the first generic of memantine was registered in Russia - Noodgeron (Israel), which is produced according to strict established regulations that comply with international Good Manufacturing Practice (GMP) standards. The indication for the use of Noogeron is moderate to severe dementia of the Alzheimer's type.

The main problem with the use of generics is the lack of evidence base, namely studies using a generic drug that confirm clinical efficacy and safety comparable to the original drug. That is, a generic can be considered effective if not only pharmacokinetic studies have been conducted (to confirm bioequivalence to the original drug, or similar bioavailability), but also studies proving therapeutic equivalence to the original drug. Clinical effect studies should be conducted for each generic drug to ensure its successful use in clinical practice. Over the 7 years of use of Noogerone in Russia (since 2010), not only extensive experience in everyday medical practice has been accumulated, but also 5 post-marketing studies have been conducted, which distinguishes the drug from other generic memantine presented on the Russian market, for which the evaluation of the results of clinical use is not was undertaken.

Let us present the main results of the 2 most significant studies of noodgeron [41, 43], confirming the successful results of its clinical study.

A 24-week (6-month) open-label post-marketing study of the efficacy and tolerability of Noogerone (20 mg/day) [41] included 44 patients suffering from moderate AD dementia and AD mixed with cerebrovascular disease. During 6 months of therapy with Noogerone at an average daily dose of 20 mg/day, the following was noted:

— a significant improvement in cognitive function according to the MMSE scale after 24 weeks of taking the drug, and according to the ADAS-Cog scale after 18 weeks (at week 24, this indicator underwent some negative dynamics, but did not decrease compared to that at the start of the study). When analyzing individual ADAS-Cog subscales after 24 weeks of therapy, a statistically significant improvement in immediate production, speech perception and following directions, orientation and memory of instructions was revealed;

— absence of progression of non-cognitive symptoms of the disease (severity of psychotic symptoms and behavioral disorders on the NPI scale);

— no decrease in the ability to self-care and daily activity of patients according to the ADCS-ADL scale;

— good tolerability of the drug, despite advanced age and high frequency of concomitant somatic diseases. The incidence of adverse events associated with taking Noogerone was 4.5%.

The authors indicate that the data obtained are comparable to the results of large randomized placebo-controlled studies of the original memantine [13, 42], which may indicate similar efficacy and tolerability of noogerone.

Another observational 12-week (3-month) study of noogerone (20 mg per day), conducted by employees of the Department of Geriatric Psychiatry of the Scientific Center for Mental Health of the Russian Academy of Medical Sciences [43], included 30 patients with moderate and moderately severe asthma. As a result of observation, the following results were demonstrated:

- on the CGI scale, 66.6% had a positive effect at the end of the study, in 36.6% the improvement was assessed as moderate and significantly pronounced;

— significant improvement in the cognitive functioning of patients compared to the initial level on the MMSE and ADAS-Cog scales;

— a significant improvement in the indicator characterizing the quality of patients’ daily activities (including eating and taking medications, dressing, personal care, as well as housework, cooking, movement, financial activities and correspondence) by 7.5%;

— significant improvement in the total score on the DAD scale, as well as in indicators assessing the planning and organization of activities and the success of performing various types of daily activities;

— significant positive dynamics of psychotic and behavioral symptoms on the NPI scale;

— reliable reduction of symptoms in relation to depression, anxiety and irritability;

— a significant reduction in the stress load on those caring for patients;

— a decrease in the group average indicator of time burden on caregivers on the RUD scale by 23.5% (with a decrease in the time spent actually serving patients) and a significant reduction in absenteeism of part-time work for working relatives providing care;

— good tolerability (transient adverse events during Noogerone therapy were observed in 2 patients).

Thus, the use of noogerone after 3 months of therapy in patients with AD at the stage of moderate and severe dementia showed safety and clinical effectiveness in relation to cognitive and daily functioning, behavioral and psychotic symptoms of dementia, as well as in reducing the burden on caregivers. The latter is particularly important because the burden of care increases as the disease progresses and behavioral and psychotic symptoms emerge. In this regard, the question of how much treatment can reduce the burden of family members associated with supervision and daily care is of particular relevance. Several studies have already been devoted to studying the possibility of improving the quality of life and health of caregivers in previous years [44–46].

The good safety profile of noogerone is of great importance, given the frequent somatic comorbidity in old age and the use of a large number of additional drugs to correct concomitant pathology. On the other hand, noogerone reduces the need for symptomatic medications used to correct behavioral, affective and psychotic symptoms due to its positive effect on them.

A personalized approach to the treatment of dementia should also take into account the pharmacoeconomic aspect. The current economic situation in Russia is characterized by a shortage of funds, therefore, from the point of view of planning and spending public health funds, as well as from the point of view of the budget of an individual family in which one of the members suffers from asthma, it is important to rely not only on the clinical effectiveness and safety of the drug, but also to confirm pharmacoeconomic feasibility.

An analysis of the Russian market of anti-dementia drugs showed that the line of generic memantine (the original drug akatinol memantine) is represented by a wide spectrum with a huge price range: noodgeron, memantine canon, maruxa, memantine, memantal, memantine, memorel, memantine-TL, memaneurin, memantine-Richter, Memikar (drugs are presented in descending order of price on the market).

Noogeron is available in a dosage of 10 mg in 3 different forms: 30 tablets per package (for the titration period of 5 mg per week), 60 tablets per package (for 1 month of therapy when taking the recommended maintenance dose of 20 mg / day) and 90 tablets per package (two packages for 3 months of therapy when taking 20 mg/day). The recommended maintenance dose of Noogeron is 20 mg/day. The maximum daily dose is 20 mg/day. Packaging with a larger number of tablets per package is convenient for the patient, as it eliminates the need to constantly worry about replenishing the drug supply and thereby improves adherence to treatment [47].

The cost of the drug is important, since memantine therapy for asthma is prescribed for a long-term maintenance purpose, often for life. Despite the fact that to achieve the desired effect, it is desirable to carry out a minimum of 6-month course of treatment, and in case of moderately severe and severe dementia, longer (up to 1 year or more) use of the drug [48], patients often interrupt treatment. Studies of therapy with antidementia drugs have shown that with asthma, 1/3 of patients stop taking the drug within the first 2 months and only half of the patients take the drug for more than 6 months [https://memini.ru/discussions/24533/].

In Russia, the high rate of drug withdrawal is associated with several reasons. The first is low public awareness of the problem of dementia and low compliance. A survey of the population showed that 42% of Russians surveyed believe that there are no drugs at all that can stop the development of senile dementia [49, 50]. A similar situation is observed in other countries: in a Korean study, more than half of the respondents (52.7%) considered dementia to be an incurable disease [51]; in a survey conducted in China, 45% of respondents expressed doubts about the effectiveness of any treatment for dementia [52]. Lack of understanding of the importance and advisability of taking medications for dementia by both the patient himself and his relatives underlies low adherence to therapy and interruption of treatment. This is fraught not only with a loss of effectiveness due to non-compliance with the dosage regimen, but also with the development of side effects due to improper resumption of treatment: for example, simultaneous administration of several doses due to the desire to “catch up” the effect due to missing previous doses or a sharp resumption of use after long break without preliminary titration [53]. In addition to reduced effectiveness, poor patient compliance has been shown to increase hospitalization [54] and mortality [55]. In addition, drug withdrawal often occurs because the patient’s relatives expect, but do not see, a quick and clear effect, which should be discussed with the doctor in advance. Often, during an outpatient appointment, incorrect tactics are observed on the part of the neurologist, namely, prescribing a suboptimal dose of 10 mg/day for continuous use or prescribing memantine in seasonal courses along with vascular, metabolic and nootropic drugs. Such harmful practice does not allow achieving the possible positive effect of taking the drug and often leads to a “collapse” of the condition. Dramatic deterioration or lack of efficacy at ineffective doses also leads to poor compliance and discontinuation by the patient. Overall, adherence to antidementia medications is 40–60%, which is similar to data for other chronic disorders [56, 57]. It is known that if long-term use of the drug is necessary, a pronounced decrease in compliance is observed 6 months from the start of therapy [58]. In other words, even timely recognition of dementia and prescription of memantine does not guarantee that the patient will take the drug regularly and for a long time. This understanding may become the basis for prescribing to the patient not an expensive original drug, but a more affordable generic, provided there is a good evidence base, for example, Noogerone.

The second reason for discontinuation of memantine therapy is related to the economic aspect. An example would be the analysis of anamnestic data of patients from one of the above-mentioned studies of Noogeron conducted on the Russian population. Of the patients who had experience with akatinol memantine, the majority (84%) discontinued treatment due to financial difficulties [41]. An attempt to save money (which can come from both the doctor and the patient and his family) is also often the basis for prescribing or taking ineffective (10 mg/day) doses. Thus, treatment in most cases requires financial optimization. Israeli memantine - noodgeron - will save up to 30% on treatment compared to the original memantine, while providing treatment with memantine with an established clinical base and proven therapeutic equivalence to the original drug [41]. As a result, by reducing economic costs, it is possible to increase adherence to asthma therapy in cases where the financial component plays a decisive role in maintaining long-term use of memantine.

Thus, the use of noogerone in Alzheimer's type dementia of moderate and severe severity is promising from a clinical and economic point of view. The appearance of the generic memantine noogerone is of great medical and social significance, as it makes effective treatment more accessible to the general population. This is in line with the World Health Organization's current strategy to support the production of quality generic drugs and their use in clinical practice to ensure access to health care.

The authors declare no conflict of interest.

Treatment regimen

◊ Dosage and dose selection

• 10 mg twice daily
• 28 mg once daily (long-acting)
• Initially 5 mg/day, increase by 5 mg every week; a dose greater than 5 mg should be divided into parts; the maximum dose is 10 mg twice a day [1].
• Long-acting: initially 7 mg once daily, can be increased by 7 mg weekly, maximum dose 28 mg once daily [1].

◊ How quickly it works

Memory improvement is not expected, and it will take months for the condition to stabilize [1].

◊ Expected result

Slows down the development of the disease, but does not stop the degenerative process.

◊ If it doesn't work

• Change the dose, switch to a cholinesterase inhibitor (galantamine, donepezil, rivastigmine) or add a cholinesterase inhibitor.
• Reconsider the diagnosis to rule out depression or non-Alzheimer's dementia [1].

◊ How to stop taking it

• There were no cases of withdrawal syndrome.
• Theoretically, discontinuation of dosage may cause memory impairment and changes in behavior that may remain uncorrected after resumption or initiation of dosage [1].

◊ Treatment combinations

• Atypical antipsychotics for behavior correction;
• Antidepressants for depression, apathy, loss of interest;
• Can be combined with cholinesterase inhibitors;
• Carbamazepine, oxcarbamazepine for behavioral disorders;

Effects of Memantine

Based on the mechanisms of action, there will be sedation (depending on the dosage), deterioration of intellectual abilities, and a slight improvement in mood.

Only people who have diseases affecting the central nervous system in one way or another will be able to experience an improvement in mental activity. Another option is impulsive, explosive people, with hyperactivity of the glutamate system. If you fall asleep from mega-popular shows and don’t yell out the window when ours are being hammered, then memantine will be more dull!

I dug around the reddit forums and found information about “flat thinking”, that when taking dosages higher than therapeutic ones, slight distortions of perception arise, felt on an emotional level. Many people write about calmness and prudence. These words can be partially confirmed by another link (https://www.ncbi.nlm.nih.gov/pubmed/22327556), where memantine in rats increased the concentration of BDNF and exhibited a stress-protective effect.

Special patient groups

◊ Patients with kidney problems

• No special dose selection is required.
• In severe renal failure, reduce the dose.

◊ Patients with liver disease

No special dose selection is required.

◊ Patients with heart disease

No special dose selection is required.

◊ Elderly patients

The same pharmacokinetics as in young patients.

◊ Children and teenagers

The use of memantine has not been studied.

◊ Pregnant women

• Risk Category B – animal studies have not shown any risk of adverse effects on the fetus, and there have been no adequate studies in pregnant women;
• Not recommended for pregnant women or those preparing to conceive [1].

◊ Breastfeeding

Memantine is not known to pass into breast milk, but all psychotropic drugs pass into breast milk. It is recommended that you stop taking memantine or stop breastfeeding [1].

Side effects and other risks

◊ Mechanism of side effects

Presumably due to excessive effects on NMDA receptors.

◊ Side effects

• Dizziness, headache;
• Constipation;
• Dangerous side effects: seizures;
• Weight gain: no;
• Sedation: no, but weakness may occur [1].

◊ What to do about side effects

Wait; Reduce the dose, switch to another drug.

◊ Long-term use

After 6 months, treatment may no longer slow the progression of Alzheimer's disease [1].

◊Addiction

No.

◊ Overdose

• There were no deaths.
• Anxiety, psychosis, visual hallucinations, drowsiness, stupor, loss of consciousness.

Expert advice

• One of two medications recommended for severe Alzheimer's disease;
• The action of memantine is similar to the natural inhibition of NDMA receptors by magnesium, so memantine is a kind of “artificial magnesium.”
• Theoretically, memantine's NMDA antagonism is strong enough to reduce the excitation of glutamate receptors characteristic of Alzheimer's disease, but not strong enough to affect the use of glutamate for plasticity, learning and memory.
• Has a related structure to amantadine, which is also a weak NMDA antagonist
• Memantadine is well tolerated and rarely causes side effects
• The consequences of 5-HT3 receptor antagonist activity have not been studied, but this may be why so few gastrointestinal side effects are observed [1]

How does memantine work?

1. Acts as an NMDAR (https://www.ncbi.nlm.nih.gov/pubmed/16368266). In an old issue about Semax, there was a study where mice lost memory when they were injected with an NMDA receptor inhibitor. Anyway, glutamate, a signal accelerator in the brain, also works through this receptor, and it seems counterintuitive to not stimulate it. What's the point you ask?

Once upon a time we already mentioned excitotoxicity, this is when excessive stimulation of the brain occurs, which does not improve memory, but rather kills the brain, nerve cells, in the literal sense. So, if a person has excessive activity of the glutamate system, then it is important to reduce the speed of transmission of nerve impulses. Technically, this can be done in many ways, if it is trivial - to increase the activity of GABA.

However, there may be a situation where glutamate works as it should, but the receptors with which it interacts (NMDA and AMPA) are too easily susceptible to it. To make it clearer, imagine a car driving at great speed. And to slow it down, you can press the brake, in our case it is the GABA system, or you can ease the pressure on the gas pedal. By “turning off” NMDA receptors, we slow down our car to normal speed, where controllability is better. This means better brain function.

In medicine, NMDAR antagonists are used primarily for anesthesia. For example, ketamine is used as a pain reliever. This anesthesia is called “dissociative anesthesia”; by the way, it is from this medical term that the so-called “dissociatives” originated. Substances with the help of which they try to “get stubborn and catch hell”, exceeding all imaginable dosages.

1. Memantine restores normal dopamine levels, when they are suppressed by drugs (https://www.ncbi.nlm.nih.gov/pubmed/25025505). There is evidence that memantine is an agonist of the dopamine receptor type 2 (D2). An agonist means it makes the receptor work more efficiently (https://www.ncbi.nlm.nih.gov/pubmed/18000814).

The D2 receptor is primarily responsible for the psychological state. With a low density of these receptors and weak activity, a person becomes prone to alcoholism, drug addiction, and depression. At a moderately high level – good mood, creative thinking, sensitivity, sentimentality. If it is too high, you begin to hear voices. Many antipsychotic drugs suppress the dopamine type 2 receptor to make a person less anxious.

1. Acts as an antagonist of serotonin receptor type 3 . This information appears in the description of the mechanism of action of Western memantine analogues, while in Russia it is not officially presented (https://www.alzforum.org/therapeutics/memantine). Typically, antagonists of this receptor are used to reduce side effects from the digestive system after chemotherapy. (https://pharmacologycorner.com/serotonin-5-ht3-receptor-antagonists/)