"Single-soldier combat" or "elite squad"? Revisit the combination treatment for Alzheimer's disease

In an accelerated population ageing environment, the rising number of Alzheimer's disease (AD) patients is of great concern to society1. Alzheimer's disease is a chronic degenerative disease that is at the forefront of drug development. Usually available in China are cholinesterase inhibitors (ChEI) represented by donepezil and kabbalatine and N-methyl-D-aspartate receptor (NMDAR) antagonist memantine. In addition, mannit sodium has also been listed in recent years. These drugs improve symptoms through different mechanisms. When monotherapy is used clinically, intolerance or unsatisfactory efficacy may occur. So, is it possible to combine two or more drugs that target different mechanisms in order to bring more benefits to patients?

The clinical benefits of the golden partner, Mei Jingang and ChEI, are considerable

Multiple studies have found additional clinical benefits in combination with ChEI compared to ChEI monotherapy.

From the perspective of efficacy, there is a potential synergy between the combination of memantine and diamond. The Cochrane database published a meta-analysis article2 in 2019 that included a total of 44 RCTs, and the results showed that, whether used in conjunction with ChEI or not, Memantine was able to comprehensively improve the three types of ABC symptoms (A- decreased functioning in daily life, B- psychobehavioral symptoms, and C-cognitive impairment) in patients with AD. Data from six RCT studies over a period of six months showed that the proportion of patients with significant clinical deterioration compared to ChEI monotherapy was significantly lower3. These improvements also have a physiological basis, with 35 patients with AD with psychobehavioral symptoms of dementia (BPSD) evaluated in one study and showed extensive improvements in cerebral blood flow in the group of combined patients4.

In terms of safety, meta-analyses have shown that combination therapy does not increase the risk of serious adverse events, or even reduces the risk of specific events5. For example, ten years of safety data from the FAERS database show that patients with combined treatment with ChEI have a significantly lower risk of bradycardia than ChEI monotherapy6.

It is worth mentioning that the efficacy and safety of combination therapy can be maintained for a long time. A prospective observational study of more than 300 patients who received standard care without drug therapy, ChEI monotherapy, and combination ChEI with memantine was followed up for four years suggested that long-term combination therapy significantly reduced cognitive and functional decline7.

Based on the benefits of multiple literature reports on combination therapy, a number of domestic guidelines and consensus clearly recommend the use of combination drugs for the treatment of patients with moderate to severe AD. For example, the "Guidelines for the Diagnosis and Treatment of Dementia and Cognitive Impairment in China (2018)" edited by Professor Jia Jianping describes that patients with moderate to severe AD with a clear diagnosis can choose memantine or the combination of memantine and donepezil and kabaraten, and for patients with severe AD with obvious psychobehavioral symptoms, ChEI and memantine are especially recommended to use chEI in combination8.

Pearl Dark Projection - Combination Therapy Is Not "Hot"

Although there is sufficient evidence for the use of combination drugs in patients with moderate to severe AD, in clinical practice, the proportion of prescriptions for domestic combination drugs is still low. From 2012 to 2013, a multicenter observational study surveyed the prescription of anti-dementia drugs and antipsychotic drugs in China and its associated factors9 by including 751 patients with cognitive impairment in 28 tertiary hospitals in 14 provinces, of which 64.8% were moderately severe AD patients, but only 14.8% of patients received the combination of memantine and donepezil.

In clinical practice, the factors that limit the combination of drugs are very complex.

Among non-medical factors, economic burden and inadequate access to medications are common. In addition, the difficulty of patients' medical treatment will also affect reasonable combination drugs, for example, the difficulty of standardizing the registration of special clinics, or the low willingness of caregivers to treat.

Medical factors also limit combinations. Although guidelines and consensus explicitly recommend combination therapy, the actual complexity of diagnosis and treatment still challenges doctors. For example, non-specialist physicians have insufficient diagnostic ability and awareness of standardized treatment, evidence of benefit from combination therapy is not widely known and recognized, or there are safety concerns about special populations (such as elderly patients, psychiatric patients, etc.) who prefer monotherapy. The rational choice of combination drugs puts forward higher requirements for the doctor's diagnosis and treatment level.

Military division guidance - how to start the combination of drugs? ·

At a national expert consultation meeting held recently, the participating experts generally agreed that reasonable combination therapy has a synergistic effect and is a powerful weapon to comprehensively improve the symptoms of AD patients and delay the progression of the disease. In their view, memantine and ChEI have additional overall efficacy, significant improvements in BPSD, few safety concerns, can delay disease progression, and reduce the risk of future combination of antipsychotics.

However, there is no uniform specification for when and how combination therapy for patients with AD is initiated. After discussion, the participating experts generally recognized:

Initiation of combination therapy in long-term follow-up patients with significant progression (supported by subjective and objective evidence) or poor tolerance of ChEI on a cheEI monotherapy basis;

For moderately to severe patients newly diagnosed (MMSE score

Some experts have also used experience to point out other situations in which combination therapy is considered, such as higher treatment expectations or delayed demand from the patient's family; ChEI single-agent disease progresses rapidly and makes it impossible to adhere to regular follow-up; diagnosed as behavioral variant AD; and the urgent need to rapidly improve cognition because BPSD is only used when transferred from the hospital to antipsychotic drugs...

The value of combination therapy is particularly prominent among the few treatment options. Therefore, experts hope to strengthen disease education for doctors and patients on the basis of ensuring the accessibility of drugs, reduce the concerns of combination drugs, and benefit more patients through reasonable combination treatment.

【Note】

MMSE: Concise Mental Status Scale

BPSD: Psychobehavioral symptoms of dementia

RCT: randomized controlled trial

References: Swipe up to view

1. Yuan Dan, et al. Effect of memantine and donepezil on cognitive function and neurotransmitters in patients with Alzheimer's disease[J].Journal of Brain and Neurological Diseases,2022,30(02):71-75.

2. McShane R, et al. Cochrane Database Syst Rev. 2019,20;3(3):CD003154

3.Wilkinson & Andersen. Dement Geriatr Cogn Disord 2007; 24: 138–145.

4.Kiyoshi K, et al. Br J Res. 2017; 4(2): 13, 1-5.

5. Schmidt R, et al. Eur J Neurol. 2015; 22(6): 889-98.

6. Shi XD, et al. Am J Alzheimers Dis Other Demen, 2016, 31: 405-12.

7. Atri A, et al. Alzheimer Dis Assoc Disord, 2008, 22: 209-21.

8. Chinese Dementia and Cognitive Impairment Writing Group, Cognitive Disorders Committee of Neurologist Branch of Chinese Medical Doctor Association. Chinese Medical Journal,2018,98(13):971-977.

9. Zhang et al. J Am Med Dir Assoc, 2021,18; S1525-8610(21)00665-4.

Lingbei Medical Department is the most beautiful reader

Approval Number: CNSM-0367

Disclaimer: The approved indications for memantine hydrochloride tablets in China are moderate to severe Alzheimer's dementia, and this series of contents is used for academic information exchange. In order to answer the inquiries and needs of doctors or update the cutting-edge progress, authoritative experts in the field are invited to read and summarize, interpret and discuss hot issues to dispel doubts.