Memantine and its role in parkinsonism, seizure, depression, migraine headache, and Alzheimer’s disease

and its


Introduction
Worldwide, Alzheimer's disease is a significant health concern that is associated with symptoms and diseases of aging (Bellenguez et al. 2022). Despite the availability of medicines that improve human health and increase lifespan in many countries, a specific cause or treatment that can stop Alzheimer's disease has not been found, and it is expected that the incidence of dementia and Alzheimer's disease will rise significantly over the next twenty years (Bellenguez et al. 2022).
The increase in the prevalence of Alzheimer's disease is also associated with a rise in high socio-health costs at the national level, which is expected to become even more significant in the future (Trevisan et al. 2019). This is a common trend for all chronic diseases, including hypertension, hyperglycemia, dementia, hyperlipidemia, uveitis (Akeel Naji 2021), and many others. Socio-health costs attributable to Alzheimer's disease increase parallel with functional impairment, cognitive impairment, comorbidity, and neuropsychiatric symptoms (Martin and Velayudhan 2020).
However, early diagnosis and treatment of Alzheimer's disease could reduce the socioeconomic cost of the disease. The goal of treatment is to delay the appearance of disease symptoms, reduce functional deterioration, improve patients' quality of life, and relieve the burden on family members and caregivers (Sonkusare 2005).
The impact of antidementia drugs, such as memantine, on cost-effectiveness can be measured through various parameters, including economic factors such as hospital admissions, delay in institutionalization, emergency care costs, need for more continuous care, and use of psychotropic drugs. Other factors are more related to the quality of life of the patient and caregiver (Atri 2019).
This review highlights the role of memantine in Alzheimer's disease, ranging from its indications and contraindications to its ability to improve cognitive, behavioral, and functional symptoms, as well as the quality of life of patients.

Memantine and mechanism of its effect discovery and its role in Alzheimer
In 1966, memantine was discovered as a drug for treating hyperglycemia to treat high blood glucose. It has been shown not to have a significant effect on decreasing blood glucose. However, after this drug was developed in the enter clinical phases due to the prospect of an effect on the treatment of parkinsonism, seizure, depression, margin headache, and finally, Alzheimer's disease (Koola 2020).
As the only non-competitive NMDA receptor antagonist currently in clinical practice, memantine can inhibit the excessive activation of NMDA receptors to reduce excitotoxicity and protect neurons without affecting the physiological activation of NMDA receptors required for cognition (Companys-Alemany et al. 2020).

Clinical Guidelines for the Use of Memantine in Dementia
Many countries and institutions have decided to use memantine to treat Alzheimer's and reduce its symptoms. According to studies, some preferred memantine anti-acetylcholine esterase drugs, while others decided to leave it alone to treat Alzheimer's and reduce symptoms. For example, not loss, both the Behavioral Neurology and Dementia Study Group and the Neuropharmacology Group recommend memantine treatment in patients with probable or possible moderate or severe AD according to the NINCDS-ADRA criteria (National Institute of Neurologic, Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association ) (level of evidence I, grade of recommendation A). It is also commented that combined use with a cholinesterase inhibitor (ACEI) in these phases is more beneficial than monotherapy with acetylcholine esterase inhibitors (level of evidence II, grade of recommendation B) (Calhoun et al. 2018;Straathof et al. 2022).

NICE guidelines on the treatment of dementia
The National Institute of Health and Care Excellence (NICE) guidelines in the United Kingdom recommend memantine monotherapy in patients with moderate AD who are intolerant or have a contraindication to using acetylcholine inhibitors in patients with AD in the severe phase of the disease (Yunusa et al. 2021;Butterworth 2022).
For patients with an established diagnosis of AD who are taking acetylcholine inhibitors, the following is included: a) Consider adding memantine with or without an acetylcholine inhibitor if you are in a moderate phase; b) Consider adding memantine to the acetylcholine inhibitor if they are in an advanced stage.
Its prescription must be made under the following conditions: a) prescriptions made by specialists such as neurologists, geriatricians, and psychiatrists; b) other health professionals, such as primary care physicians, if they have an expert degree in the diagnosis and treatment of AD; and c) do not suspend treatment with acetylcholine inhibitors in people with AD solely based on advanced disease.

Cochrane: Memantine as a treatment for dementia
Memantine benefits patients with moderate to severe AD, and this benefit affects cognition, functionality, and psychological and behavioral symptoms. The association of memantine and acetylcholine inhibitors produces less deterioration than a placebo. However, memantine is probably not better in patients with mild AD than in a placebo.
Overall, the evidence for memantine for AD is of high quality, coming from many trials in thousands of pa-tients. We can be confident in the AD results, but this is not the case in patients with other types of dementia (Calhoun et al. 2018).

Memantin's mechanism of action
Memantine is a non-competitive antagonist of NMDA (N-methyl-D-aspartate acid) glutamatergic receptors. These receptors are calcium channels, and through their action, high levels of glutamate are regulated, ultimately responsible for neuronal dysfunction and death (Abdulameer et al. 2022;Al-kuraishy et al. 2022).
Several studies are trying to understand the mechanism of action of memantine and its neuroprotective effects that decrease the level of excitatory neurotransmitters. So the use of memantine is not limited to Alzheimer's only. In the Straathof et al. study, memantine could help treat obsessive-convulsive disorder (OCD) and reduce abnormalities in dopaminergic neurons (Straathof et al. 2022).
Physiologically, memantine and magnesium occupy the same NMDA receptor and are mutually exclusive as long as the channel is not blocked in the presence of both compounds (Thangabalan et al. 2013;Salim Mahmood et al. 2022). Receptor blockade's amplitude and speed are dose-dependent. Growing data indicates that neurodegenerative dementia symptoms and disease development are influenced by dysfunctional glutamatergic neurotransmission, notably in NMDA receptors (Fig. 1).

Indications for starting treatment
Memantine has been shown to improve cognition, global clinical status, activities of daily living, and behavioral changes in moderate and severe AD. Like acetylcholine inhibitors, although the overall benefit is modest, the interindividual response to memantine is variable (level of evidence I, grade of recommendation A) (Kamepalli Sujana et al. 2012;Al-Hussaniy et al. 2022d;Naji et al. 2022;Sai 2022).

Posology
The dose of memantine is well tolerated, reaching a maximum dose of about 28 mg daily. However, the dose can gradually increase every week to reach the maintenance dose to produce a better-tolerated effect with minimal side effects, and this can be achieved by gradually increasing the dose to 5 mg each week for the first three weeks as follows: memantine 5 mg at breakfast in the first week followed by 10 mg in the second, 15 mg for the third week, then the maintenance dose can be achieved in week four. The recommended maintenance dose is 20 mg per day. An equivalent liquid formulation can be adjusted easily and is suitable for patients that cannot tolerate tablet formulation (George and Kachappillil 2020;Rossignol et al. 2021).
The memantine tablet can be administered with or without food. However, the dose of memantine must be adjusted in patients with renal impermeant, especially when creatinine clearance reaches approximately (50 ml/ minute / 1.73 m 2 ) in this case, the daily dose of memantine is approximately 10 mg per day (Table 1).

Treatment withdrawal
There are no evidence-based guidelines on when to withdraw this drug. It is recommended to evaluate its effect after six months of treatment. It is recommended to stop treatment if agitation, akathisia, or other neuropsychiatric symptoms appear and if the patient worsens globally faster than without treatment (Reeve et al. 2021).

Main contraindications or precautions
It is generally a well-tolerated drug, with adverse effects similar to placebo in some studies. The most frequent adverse effects are dizziness, constipation, drowsiness, headache, hypertension, and agitation. In patients with severe renal insufficiency, the dose should be reduced. It has no absolute contraindications, but caution must be exercised in epilepsy, renal failure, or urinary retention ( Table 2).

Improvement of psychological and behavioral symptoms associated with dementia and cognitive symptoms
Psychological and behavioral symptoms associated with dementia are very common throughout the disease, appearing in up to 80% of patients during its evolution. A meta-analysis showed a significant improvement in agita-

Presentations
Posology -Tablets 10 and 20 mg -Tablets 5, 10, 15, and 20 mg (initiator pack) -Or dispersible tablets 10 and 20 mg -Oral solution 5 mg/actuation 5 mg/day in the first week, increasing by 5 mg every week, up to 20 mg/day in 1 or 2 doses (10 mg in renal failure) tion, illusions, disinhibition, and sleep-wake rhythm disorders compared to controls, slightly superior in managing hallucinations and irritability. In contrast, it presents similar results to controls in managing negative symptoms (dysphoria, anxiety/phobia, apathy, aberrant motor behavior, and eating behavior disorders) (Najim et al. 2021;Kim et al. 2022).
Regarding cognitive symptoms, a recent study revealed that the best drug to combat cognitive deterioration was memantine, followed by galantamine.

Functional improvement of patients and quality of life
The main objective of patients with dementia is to maintain functional autonomy. Evidence-based medicine recommends memantine, ACE inhibitors, physical exercise, and dyadic intervention to prolong functional autonomy and delay institutionalization. In patients treated with memantine monotherapy or biotherapy, post hoc analysis shows maintenance of daily activities compared to placebo, with consequent delay in institutionalization (Shaw et al. 2018).
On the other hand, memantine treatment has been shown to reduce caregiver stress and caregiver care time.
In the few studies in this regard, combined therapy further enhances the concept of quality of life. The appropriate choice of treatment and therapeutic expectations is crucial, with real goals for the patient and the caregiver.
In the multicenter DOMINO-AD study ("Donepezil and Memantine in Moderate to Severe Alzheimer's Disease study"), variables related to the interruption of donepezil treatment or the start of memantine treatment were collected. Both patients who continued taking donepezil and those who started memantine showed less deterioration on the standardized Mini-Mental Test (SMMSE; p < 0.001) and on the Bristol Activities of Daily Living Scale (BADLS; p < 0.001) than those who discontinued donepezil or did not take memantine. Combination therapy (donepezil and memantine) was not significantly superior to donepezil monotherapy for primary or secondary endpoints. The post-analysis of the study data showed that abrupt discontinuation of donepezil increased the risk of worsening the condition within a few weeks of discon-tinuation and increased hospital admissions during the research period. Taken together, this is the most stressful moment associated with the poor quality of life that their caregivers envision. It is the most conflictive moment related to a worse quality of life perceived by their caregivers (Rajesh Kumar et al. 2014;Katsayal et al. 2021).

Impact in terms of healthcare care costs
Talking about dementia in economic terms is always undesirable. However, the reality is that it is one of the clinical entities that cause the most direct and indirect spending at the socio-health level. Combined therapy (ACEI and memantine) continues to be the most cost-effective approach from a health and social perspective, superior to treatment in monotherapy with ACE inhibitors. Studies show the real economic benefits of anti-AD therapies, both in favor of changing ACE inhibitors for memantine and continuing with ACE inhibitors (donepezil) (Katsayal et al. 2021;Sahu et al. 2021).
There are few studies concerning drug prescription in patients admitted to nursing homes. In indirect analyzes of health costs focused on drugs, it has been observed that the combination of therapies (ACE inhibitors and memantine) is the most cost-effective in reducing the costs derived from institutionalization in a residential center; therefore, its impact is not only economic but also in terms of health standards (Sahu et al. 2021).

Role of memantine in other neurodegenerative entities: frontotemporal dementia
Reviewing publications on the possibility of implementing symptomatic treatment in frontotemporal dementia (FTD) with memantine, a study published in 2018 brings together the results of clinical trials and case studies. The first, published in 2008, includes a family case of FTD, a behavioral variant, treated with memantine 10 mg twice daily. In this case, with a pathogenic mutation (R406W) in the MAPT gene (microtubule-associated protein tau), the author suggests that memantine could stabilize the progression of the symptoms of the disease.
However, the multicenter, randomized, double-blind, placebo-controlled clinical trial NCT00545974 evaluated the efficacy of memantine in mild to moderate FTD. It was concluded that memantine did not reduce symptoms in this type of dementia (Bang et al. 2015).
The latest Cochrane publication on the role of memantine in dementias addresses its potential use in FTD. It concludes that there is significantly little certainty in the evidence of its beneficial clinical effect on the GCR (global clinical rating) and behavioral symptoms compared to placebo. Similarly, there are no differences in cognitive function. However, for all results in efficacy, there is uncertainty, and the confidence interval is consistent with more than one conclusion. On the other hand, they con- sider a great deal of discontinuity in the memantine group regarding therapeutic compliance (compared to placebo), which may be a source of confusion (Bang et al. 2015).

Basic and memantine research
Although memantine has been a consolidated drug in the symptomatic treatment of dementia for decades, basic research, essential in translational science, continues to focus on this molecule, revealing promising and interesting results in animal models and opening the possibility of a different clinical approval from the current one (Babiloni et al. 2013).
In a very recent article from 2021, this ability to impact the biological bases of AD is revealed, which, until now, is an enigma. In this work, a benefit is evidenced in the preclinical transgenic mouse model (homozygous Tg4-42) subjected to chronic treatment for four months with memantine at the level of cognitive performance (learning and memory tasks), behavioral symptomatology and pathological correlate, observing a reduction in loss of neurons in CA1 of the hippocampus, as well as decreasing neurogenesis impairment in the dentate gyrus. This effect, key in the mechanisms of neurodegeneration, reopens the debate on the potential usefulness of memantine in earlier phases of Alzheimer's disease, not only because of the clinical benefit described but also because of its action on the biology of the disease itself, making it a more than symptomatic treatment (Babiloni et al. 2013;Rosini et al. 2016;Al-Kuraishy et al. 2022).

Memantine and migraine headache
In the past, memantine was suggested to treat migraine headaches; However, the researchers show that some migraine sufferers have benefited from using memantine to treat migraine headaches (Shanmugam et al. 2019;Mahmood et al. 2023). Migraine headaches are characterized by moderate or severe head pain lasting any-where from 4 hours to 7 days. The severity of migraine headaches can vary depending on patient factors such as age and genetics. Memantine has been found effective in treating chronic migraine sufferers who have failed other treatment options. This drug blocks certain receptors in the brain that can relieve pain caused by migraines and cluster headaches (Al_hussaniy et al. 2022a, c;Al_hussaniy 2023;Mahmood et al. 2023).
Memantine has also been found useful in treating depression; however, there are debates regarding its effectiveness for this purpose. Major depressive illness, bipolar disorder, postpartum depression, and seasonal affective disorder are just a few examples of the various forms of depression (Awad et al. 2022;Al_hussaniy et al. 2022b;Hussein et al. 2023). Depression is characterized by extreme sadness or a sense of worthlessness that interferes with normal daily activities. Memantine works by blocking neurotransmitters that cause brain cell damage and death when levels are too high. It also prevents excess glutamate from binding to NMDA receptors and causing inflammation and scarring in the brain. On the other hand, some believe that memantine is not very effective for depression because it only works for some patients and may cause side effects such as dizziness or headache in some patients (Hsu et al. 2022;Tawfeeq et al. 2022).

Conclusions
The indications for the use of memantine have been reviewed according to different clinical guidelines. The positive impact of the prescription of this drug in monotherapy and dual therapy in patients with Alzheimer's disease, according to the classic parameters of behavioral neurology, is highlighted. Possible indications in other entities, such as frontal lobe type dementia (DFT), have been discussed. It ends by opening the debate on its potential beneficial effect in earlier phases, both clinically and biologically, thanks to current basic science.