This is the second report on the benefit or risk of treatment with anti-Alzheimer’s disease (AD) drugs (AADs). As a tool for monitoring citizen health, we use information from the National Health Service (NHIS) for all citizens via an information retrieval engine to link International Classification of Diseases (ICD)-10 codes and death tables of AADs with big data to create a standard comparison between AADs and deaths over 12 years. According to the International Classification of Disease-10 (ICD-10) codes, the correlation between the trend in the number of deaths and the number of deaths per 100,000 people was analyzed via the National Health Insurance System (NHIS) through the decision of the Open Data Mediation Committee of South Korea (case number: 2020-029) and information disclosure (20240110). The Dementia Management Act (DMA) in South Korea was enacted in 2012 and all dementia subjects are registered at Central Dementia Center. In completely blinded randomized states, we enrolled subjects from 2012 (the year of the Dementia Management Act) to 2018 (the year of the Dementia National Responsibility System was implemented). We observed a correlation between the AD and AAD groups from 2005 to 2019 on Sorok Island and from 2010 to 2021 on the NHIS of South Korea. This study investigated the increase and decrease in mortality in AD patients with AAD. We analyzed the mortality per 100,000 people with the R2. A simple linear equation was applied to trace the increase (+) or decrease (-) in deaths with the Friedman and Kolmogorov‒Smirnov tests for decisions on the listed, delisted, and sustainable drugs based on R2 > 0.75. Total deaths from AD caused by AAD decreased (R2, 0.993) from 2010 to 2021. From 2012 to 2018, the drugs listed to reduce deaths were fluoxetine (R2, 0.826), escitalopram (0.955) and galantamine (0.825) in South Korea. The delisted drugs used were donepezil (0.861), rivastigmine (0.754), risperidone (0.816), quetiapine (0.977), and haloperidol (0.973). The sustainable drugs used were memantine (0.108), olanzapine (0.124), fluvoxamine (0.001), oxcarbazepine (0.52), and trazodone (0.331). With the 12-year trend, galantamine, fluoxetine, could be therapeutics for AD, and sertraline and aripiprazole could be therapeutics; however, additional observation is needed. Deaths and AADs based on NHIS big data could be useful for safe dementia care.
Article
Reporting on the Safety of Dementia Care for 2010-2021 in South Korea
https://doi.org/10.21203/rs.3.rs-4222939/v1
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This study has been conducted to determine the potential clinical impact of elderly patients receiving care for continuing Alzheimer’s disease (AD) and related anti-AD drugs (AADs) in a real-life setting in South Korea 1. Older adult patients living in large communities with AADs survive with a decreased mortality risk 2. Atypical antipsychotic medications are widely used to treat delusions, aggression, and agitation in people with dementia. The absolute effect of these drugs on the risk of cerebrovascular adverse events, rapid cognitive decline, and mortality has increased with their use 3 4. Antipsychotic drug-induced acute extrapyramidal syndromes and the late onset tardive dyskinesia 5 6. The life expectancy of dementia patients at the Sorokdo National Hospital on Sorok Island in South Korea has gradually decreased from 2005 to 2019 1 7. In a nationwide dementia and AADs study from 2012 to 2018, escitalopram and fluoxetine decreased the number of deaths, according to the R2 > 0.75. Memantine, olanzapine, sertraline, and aripiprazole were sustainable, and donepezil, rivastigmine, risperidone, quetiapine, and the masked group (fluvoxamine, galantamine, haloperidol, oxcarbazepine, and trazodone) increased deaths, with an R2 > 0.75 1. It is necessary to observe and observe the decreased deaths of SSRIs prescribed with acetylcholine esterase inhibitors (AChEIs) or memantine such as Escitalopram (R2, 0.955), Fluoxetine (R2, 0.826), Sertraline (R2, 0.274), and Aripiprazole (R2, 0.576) 1.
Clinical practice has changed with the approval of broader and more satisfactory treatment options, such as AChEIs and memantine 8. AChEIs are associated with reduced mortality risk 9 10 11 12 13. However, the importance of those medications relative to no treatment or an alternative psychotropic agent is still unclear. There is no study that can prove whether the mortality has decreased because of the SSRIs prescribed with AChEIs or memantine or antipsychotic drug. Therefore, we analyzed the NHIS data of all AAD and the deaths of all Koreans from 2010 to 2021.
The National Agency approved this study for the management of life-sustaining treatment, which certified that the life-sustaining treatments were managed properly (Korea National Institute for Bioethics Policy (KoNIBP) approval number P01-202007-22-006).
The Dementia Management Act (DMA) in South Korea was enacted in 2012 after "The war against Dementia in 2008". In 2018, the National Responsibility System for Dementia was implemented 14. The total number of persons with dementia were eligible for national health insurance and medical benefits in South Korea from 2010 to 2021. According to the DMA, all subjects are registered at Central Dementia Center (Table S29). The government provided support for the economic burden of dementia patients by Article 12 (1) of the DMA and the NHIS reimbursed the cost of AAD and made almost free. Medical staffs prescribed AADs in a completely blinded state, and DMA randomized the subjects and AADs.
As a tool for monitoring citizen health, we use information from the NHIS for all citizens via an information retrieval engine to link the International Classification of Diseases (ICD)-10 codes and death tables with big data to create a standard comparison time series trend graph of the number of deaths per 100,000 people from 2010 to 2021.
We used the same methodology for the comparison as that used in the first study 1. According to the Korea Drug Code of Medicine, the AADs used for symptomatic relief were donepezil hydrochloride, rivastigmine, galantamine, and N-methyl-D-aspartate (NMDA) receptor antagonists. One group of AD drugs for psychological symptoms is antidepressants, namely, the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline, aripiprazole, escitalopram, and fluvoxamine. The other groups for psychological symptoms included olanzapine, risperidone, quetiapine, haloperidol, oxcarbazepine, and trazodone. (Table S3)
Per the Information Disclosure Act, we requested information disclosure from the Korea Disease Control and Prevention Agency (registration number 9318128). After the mediation of the Open Data Mediation Committee (Case number: 2022-015) and information disclosure (20240110), the NHIS disclosed the death toll and prescriptions of the following drugs: fluvoxamine, galantamine, haloperidol, oxcarbazepine, and trazodone. With the ICD-10 codes, the correlation between death and AD drugs was analyzed from 2010 to 2021 through the coordination of the Open Data Mediation Committee (case number: 2020-029). (Table S4)
We analyzed the deaths per 100,000 people with an R2 calculator for all AD drugs, SSRIs, and other types of drugs. The same criterion was used: 0.75 of the R2 of the first report 1. The Friedman test for repeated measures was used to test for of the dependent variable of the groups receiving symptomatic relief (Table S2, S3). The Kolmogorov‒Smirnov test was applied to measure the difference from the normally distributed data between groups, and the results were considered significant at p < 0.01.
We analyzed the total deaths of 100,000 people with AD (R2, 0.993) from 2010 to 2021 via the simple linear equation − 247*x + 5018 R2 = 0.993. Owing to the active efforts of the Korean government, individuals with mild cognitive impairment (MCI) and early-stage AD were registered; the denominator increased significantly, and the number of deaths decreased from 2010 to 2021. AChEIs were used for mild and moderate AD (MMSE score 10–26), and memantine was used for moderate and severe AD (MMSE score 20 or less). As shown in Table S29-6, there were 56,174,057 donepezil prescriptions in 2019, and 789,2440 simultaneous prescriptions were given for donepezil and memantine. There were 1,967,039 galantamine prescriptions, and 313,882 concurrent galantamine and memantine prescriptions were used. Memantine is a drug used in seriously ill patients and was concurrently prescribed donepezil in 14.5% of all donepezil patients and galantamine in 16.0% of all galantamine patients. In the case of rivastigmine, 2,364,961 cases were prescribed, and 563,054 cases were concurrent prescriptions, or 23.8%. However, the number of deaths per 100,000 people was 14,503.3 in 2019 for donepezil, which had the smallest number of concurrent prescriptions (Table S7); 6,625.5 for galantamine, which had the median number of deaths (Table S9); and 12,296.2 for rivastigmine, which had the largest number of deaths (Table S8). This confirms that concurrent prescription of memantine does not affect the death toll. Because the NHIS sample comprises the entire population, the number of deaths per 100,000 people in 2019 is significant as follows: 14,503.3 for donepezil, 12,296.2 for rivastigmine, 6,625.5 for galantamine, and 15,938.3 for memantine, as shown in Table 1.
| year | Donepezil* | Rivastigmine* | Galantamine* | Memantine* |
|---|---|---|---|---|
| 2010 | 12988.0 | 9665.4 | 9180.0 | 17390.9 |
| 2011 | 12832.6 | 8684.1 | 9612.0 | 16834.2 |
| 2012 | 13058.2 | 9832.4 | 9457.6 | 17284.2 |
| 2013 | 13002.2 | 9803.1 | 8738.8 | 16678.4 |
| 2014 | 13010.7 | 9419.9 | 8867.3 | 15216.0 |
| 2015 | 13547.0 | 11883.9 | 8378.7 | 15535.4 |
| 2016 | 13611.3 | 11136.9 | 6959.3 | 15488.0 |
| 2017 | 14339.4 | 11881.2 | 7270.6 | 16337.2 |
| 2018 | 14851.2 | 12445.0 | 7306.9 | 16363.1 |
| 2019 | 14503.3 | 12296.2 | 6625.5 | 15938.3 |
| 2020 | 16160.2 | 12551.1 | 7341.1 | 17666.4 |
| 2021 | 16882.1 | 12712.9 | 6927.1 | 18016.7 |
| Sum | 168786.20 | 132312.10 | 96664.90 | 198748.80 |
| Mean | 14065.52 | 11026.01 | 8055.41 | 16562.40 |
| SD | 1335.50 | 1449.57 | 1090.88 | 911.06 |
| 95% CI | 6.37 | 7.81 | 6.88 | 4.01 |
| ( | 14059.15 | 11018.20 | 8048.53 | 16558.39 |
| ) | 14071.89 | 11033.82 | 8062.29 | 16566.41 |
| 1p-value | 0.52348 | 0.47369 | 0.36391 | 0.97046 |
| 2Kolmogorov-Smirnov Test (D) | 0.22213 | 0.23112 | 0.25299 | 0.13048 |
| 3Skewness Kurtosis Normality | 1.161857 0.421383 significantly from that which is normally distributed. | -0.305275 -1.689647 significantly from that which is normally distributed. | 0.159221 -1.785866 significantly from that which is normally distributed. | 0.052106 -1.152865 significantly from that which is normally distributed. |
| 4The Friedman Test between four groups | The X2r statistic is 34.9 (3, N = 12). The p value is < .00001. The result is significant at p < .01. | |||
| *Deaths per 100,000 population. 1The p value quantifies this probability, with a low probability indicating that the sample diverges from a normal distribution to an extent unlikely to arise merely by chance. 2The test statistic (D) provides a measurement of the divergence of your sample distribution from the normal distribution. The higher the value of D is, the less probable it is that your data are normally distributed. 3The nearer both these are to zero, the more likely it is that your distribution is normal. 4The Friedman test is a nonparametric alternative to one-way ANOVA with repeated measures. | ||||
The trends of deaths associated with donepezil, rivastigmine, galantamine, and memantine use.
The DMA changed the death toll with donepezil prescriptions per 100,000 from 12.988 to 16,882, rivastigmine from 9,665 to 12,713, memantine from 17,391 to 18,017, and galantamine from 9,180 to 6,927. Donepezil and rivastigmine increase the number of deaths. Memantine has no relationship with the death toll, as described in a previous report 1. However, galantamine decreased the number of deaths. The Kolmogorov‒Smirnov test results of the four groups were significant, which indicated that the bacteria were normally distributed, as shown in Table 1 and Fig. 1. The Friedman test of X2 yielded a p value < .00001, which was significant at p < .01. (Table S12)
Trends in deaths associated with fluoxetine, sertraline, escitalopram, and fluvoxamine use.
SSRIs have been prescribed for treating underlying diseases and symptoms of AD. The death toll of SSRIs ranged from 1,149 to 825 for fluoxetine, from 1,876 to 1,395 for sertraline, from 2,242 to 2,307 for escitalopram, from 1,337 to 984 for fluvoxamine, and from 1,312 to 1,085 for aripiprazole. All the SSRIs decreased the death toll. The results of the Kolmogorov‒Smirnov test were significant for all five groups, which indicated that they were normally distributed, as shown in Table 2 and Fig. 2. The Friedman test of X2 and p value are significant at p < .01. (Table S19)
| year | Fluoxetine* | Sertraline* | Escitalopram* | Fluvoxamine* | Aripiprazole* |
|---|---|---|---|---|---|
| 2010 | 1148.50 | 1875.70 | 2241.80 | 1336.70 | 1311.90 |
| 2011 | 1044.60 | 1717.20 | 2297.10 | 1441.10 | 1337.50 |
| 2012 | 1050.10 | 1616.30 | 2324.70 | 1476.00 | 1249.70 |
| 2013 | 1026.40 | 1641.50 | 2322.10 | 1522.40 | 1258.40 |
| 2014 | 1040.90 | 1756.20 | 2257.60 | 1642.80 | 1143.70 |
| 2015 | 1030.30 | 1642.30 | 2227.30 | 1417.70 | 1291.30 |
| 2016 | 964.10 | 1633.40 | 2155.00 | 1832.20 | 1138.50 |
| 2017 | 877.50 | 1606.10 | 2165.00 | 1627.90 | 1088.10 |
| 2018 | 871.00 | 1528.00 | 2090.20 | 1365.00 | 1083.70 |
| 2019 | 810.80 | 1405.40 | 2036.00 | 1620.90 | 1029.50 |
| 2020 | 996.40 | 1473.60 | 2386.80 | 1502.70 | 1144.60 |
| 2021 | 825.00 | 1394.60 | 2306.60 | 984.30 | 1085.30 |
| Sum | 11685.60 | 19290.30 | 26810.20 | 17769.70 | 14162.20 |
| Mean | 973.80 | 1607.53 | 2234.18 | 1480.81 | 1180.18 |
| SD | 104.87 | 141.30 | 104.51 | 208.78 | 104.11 |
| 95% CI | 1.90 | 1.99 | 1.25 | 3.07 | 1.71 |
| ( | 971.90 | 1605.53 | 2232.93 | 1477.74 | 1178.47 |
| ) | 975.70 | 1609.52 | 2235.43 | 1483.88 | 1181.90 |
| 1p-value | 0.65427 | 0.8601 | 0.90611 | 0.90528 | 0.51977 |
| 2Kolmogorov-Smirnov Test (D) | 0.19982 | 0.16246 | 0.15193 | 0.15214 | 0.22278 |
| 3Skewness Kurtosis Normality | -0.268186 -0.876854 significantly from that which is normally distributed. | 0.122792 -0.121631 significantly from that which is normally distributed. | -0.571468 -0.403589 significantly from that which is normally distributed. | -0.882363 2.45184 significantly from that which is normally distributed | 0.216978 -1.500598 significantly from that which is normally distributed. |
| 4The Friedman Test between five groups | The X2r statistic is 44.8667 (4, N = 12). The p value is < .00001. The result is significant at p < .01. | ||||
| *Deaths per 100,000 population 1The p value quantifies this probability, with a low probability indicating that your sample diverges from a normal distribution to an extent unlikely to arise merely by chance. 2The test statistic (D) provides a measurement of the divergence of your sample distribution from the normal distribution. The higher the value of D is, the less probable it is that your data are normally distributed. 3The nearer both these are to zero, the more likely it is that your distribution is normal. 4The Friedman test is a nonparametric alternative to one-way ANOVA with repeated measures. | |||||
Trends in deaths associated with olanzapine, quetiapine, haloperidol, oxcarbazepine, and trazodone use.
Psychotropic medicines have been prescribed for the symptoms of AD. The death tolls were olanzapine from 4,375 to 5066, risperidone from 4,922 to 7,505, quetiapine from 7,598 to 11,820, haloperidol from 11,212 to 20,117, oxcarbazepine from 6,516 to 6,275, and trazodone from 3,079 to 3,304. All psychotropic medicines increased the death toll. The Kolmogorov‒Smirnov test results for the five groups were significant, which indicated that the patients were normally distributed, but the patients in the risperidone group were not normally distributed, as shown in Table 3 and Fig. 3. The Friedman test (olanzapine, quetiapine, haloperidol, oxcarbazepine, and trazodone) results for X2 and the p value are significant at p < .01. (Table S27)
| year | Olanzapine* | Risperidone** | Quetiapine* | Haloperidol* | Oxcarbazepine* | Trazodone* |
|---|---|---|---|---|---|---|
| 2010 | 4374.5 | 4922.2 | 7598.2 | 11211.7 | 6515.7 | 3078.9 |
| 2011 | 4429.2 | 4823.8 | 7819.2 | 11370.1 | 6120.2 | 3029.0 |
| 2012 | 4933.4 | 4980.6 | 8718.6 | 12058.0 | 6747.2 | 2963.6 |
| 2013 | 5258.2 | 4930.9 | 9256.2 | 12826.1 | 6034.7 | 2972.7 |
| 2014 | 5163.6 | 4874.9 | 9444.0 | 13316.8 | 6099.6 | 2890.9 |
| 2015 | 4734.7 | 5129.9 | 9642.0 | 14268.2 | 6562.9 | 2936.7 |
| 2016 | 5034.2 | 5203.8 | 9937.0 | 14914.5 | 6656.6 | 2900.3 |
| 2017 | 4923.3 | 5314.4 | 10406.8 | 15965.8 | 7612.1 | 2943.0 |
| 2018 | 4937.2 | 5349.0 | 10520.0 | 16811.0 | 7333.4 | 2897.8 |
| 2019 | 4978.0 | 5279.6 | 9579.4 | 16543.2 | 6943.0 | 2755.2 |
| 2020 | 5154.2 | 7912.8 | 11735.7 | 19405.9 | 7284.8 | 3417.7 |
| 2021 | 5066.0 | 7504.8 | 11819.5 | 20116.8 | 6274.5 | 3303.7 |
| Sum | 58986.50 | 66226.70 | 116476.60 | 178808.10 | 80184.70 | 36089.50 |
| Mean | 4915.54 | 5518.89 | 9706.38 | 14900.68 | 6682.06 | 3007.46 |
| SD | 276.23 | 1041.96 | 1316.42 | 2959.63 | 522.89 | 184.55 |
| 95% CI | 2.23 | 7.94 | 7.56 | 13.72 | 3.62 | 1.90 |
| ( | 4913.31 | 5510.96 | 9698.82 | 14886.96 | 6678.44 | 3005.55 |
| ) | 4917.77 | 5526.83 | 9713.94 | 14914.39 | 6685.68 | 3009.36 |
| 1p-value | 0.32492 | 0.02972 | 0.99326 | 0.97413 | 0.95876 | 0.4038 |
| 2Kolmogorov-Smirnov Test (D) | 0.2617 | 0.40095 | 0.11298 | 0.12857 | 0.1357 | 0.24464 |
| 3Skewness Kurtosis Normality | -1.060511 0.412013 significantly from that which is normally distributed. | 1.953674 2.539917 This provides good evidence that your data is not normally distributed. | 0.072726 -0.307183 significantly from that which is normally distributed. | 0.486603 -0.737203 significantly from that which is normally distributed | 0.45597 -0.905645 significantly from that which is normally distributed. | 1.292697 1.483183 significantly from that which is normally distributed. |
| 4The Friedman Test between five groups** | The X2r statistic is 48 (4, N = 12). The p value is < .00001. The result is significant at p < .01. | |||||
| *Deaths per 100,000 population **Risperidone was excluded from the Friedman test. 1The p value quantifies this probability, with a low probability indicating that the sample diverges from a normal distribution to an extent unlikely to arise merely by chance. 2The test statistic (D) provides a measurement of the divergence of your sample distribution from the normal distribution. The higher the value of D is, the less probable it is that your data are normally distributed. 3The nearer both these are to zero, the more likely it is that your distribution is normal. 4The Friedman test is a nonparametric alternative to one-way ANOVA with repeated measures. | ||||||
The graph of deaths per 100,000 people presents very interesting results. Compared to the number of deaths of 100,000, the number of users of memantine, a treatment for patients with moderate to severe AD, was the highest, and there was no significant difference in increase or decrease; therefore, it served as a baseline. These findings prove that the results of this research analysis are scientific. The trends in deaths and AADs showed that the incidences of donepezil, rivastigmine, haloperidol and quetiapine increased, but the incidences of galantamine, fluoxetine, sertraline, and aripiprazole steadily decreased the number of deaths per 100,000 people, as shown in Fig. 4.
Analyzing the risk of death for decision
The number of deaths per 100,000 people who took donepezil increased by 1.14 times (linear Eq. 309*x + 12704, R2 0.861). (Table S7, Fig S1) Donepezil needs to be delisted.
The number of deaths associated with rivastigmine increased by 1.27 (linear Eq. 490*x + 9446, R2 0.754). (Table S8, Fig. S2) Rivastigmine needs to be delisted.
The number of deaths who took galantamine decreased by 0.773 (linear equation − 403*x + 9350, R2 0.825). (Table S9, Fig. S3) Galantamine might be a therapeutic for AD but could be a therapeutic for AD according to the 12-year trend line shown in Fig. 1.
The number of deaths who took memantine was 0.947 (linear equation − 113*x + 16469, R2 0.108). (Table S10, Fig. S4) Memantine is sustainable.
The number of patients who fluoxetine decreased by 0.829 (linear equation − 32.6*x + 1078, R2 0.826). (Table S13, Fig S6) Fluoxetine needs to be listed, and could be therapeutics for AD over 12 years’ trend line in Fig. 2.
The number of deaths in patients who sertraline decreased by 0.945 (linear equation − 16.4*x + 1681, R2 0.274). (Table S14, Fig. S7) Sertraline is sustainable but might be therapeutic for AD according to the 12-year trend line in Fig. 2.
The number of deaths associated with escitalopram decreased by 0.899 (linear equation --40*x + 2340, R2 0.955). (Table S15, Fig. S8) Escitalopram needs to be listed but might be sustainable according to the 12-year trend line in Fig. 2.
The number of deaths in patients who took fluvoxamine was 0.925 (linear Eq. 2.41*x + 1548, R2 0.001). Fluvoxamine is sustainable (Table S16, Fig. S9).
The number of deaths in patients who took aripiprazole decreased by 0.867 (linear equation − 30.1*x + 1269, R2 0.576). (Table S17, Fig. S10) Aripiprazole is sustainable but might be therapeutic for AD according to the 12-year trend line in Fig. 2. (Table S18, Fig. S11)
The number of deaths who took olanzapine was 1.001 (linear equation − 28.1*x + 5082, R2 0.124) from 2012 to June 2018. (Table S20, Fig S12) Olanzapine is sustainable.
The number of deaths who took risperidone increased by 1.074 (linear Eq. 78.6*x + 4876, R2 0.816). (Table S21, Fig S13) Risperidone needs to be delisted.
The number of deaths associated with quetiapine increased by 1.207 (linear Eq. 293*x + 8825, R2 0.977). (Table S22, Fig S14) Quetiapine needed to be delisted.
The number of deaths who took haloperidol increased by 1.394 (linear Eq. 791*x + 11937, R2 0.993). (Table S23, Fig S15) Haloperidol needed to be discontinued.
The number of deaths who took oxcarbazepine increased by 1.0869 (linear Eq. 195*x + 6135, R2 0.52). (Table S24, Fig S16) Oxcarbazepine is sustainable.
The number of deaths who took trazodone was 0.978 (linear equation − 8.84*x + 2956, R2 0.331). (Table S25, Fig S17) Trazodone is sustainable.
The results from 2012 to 2018 are summarized in Table 4 and Fig. 5.
‘Listed’ means the NHIS will reimburse available symptomatic drugs against AD. Fluoxetine, escitalopram, and galantamine, as listed drugs, decreased the number of deaths (R2 > 0.75). ‘Delisted’ means that the NHIS will no longer reimburse available symptomatic drugs against AD. The use of donepezil, rivastigmine, risperidone, quetiapine, or haloperidol as delisted drugs increased the number of deaths at R2 > 0.75. ‘Sustainable’ means that the NHIS will observe whether to reimburse available symptomatic drugs against AD. The use of memantine, olanzapine, sertraline, aripiprazole, fluvoxamine, oxcarbazepine, and trazodone as substantiable drugs was sustainable.
Evolution of the evidence on the effectiveness of AChEIs on the basis of the life expectancy of patients on Sorok Island from 2005 to 2019
The comparator of best supportive care might be cognition, function, behavior, or global impact. However, most randomized clinical trial (RCT) results for donepezil, galantamine, rivastigmine, and memantine changed from findings in 2004 to findings in 2010, with a quantified statistically significant benefit or a quantified trend toward benefit 15. AChEIs have frequent (1–10%) side effects, such as pharyngitis, pneumonia, increased cough, and bronchitis 16 17.
Patients with Hansen’s disease (HD) lived on Sorok Island for a lifetime. According to the health checkup information from 2005 to 2019, a total of 1321 people resided there, and the average age was 84.3 years (mean (M) 84.3 years, standard deviation (SD) 17.1, 95% confidence interval (CI): 83.6–85.0). As shown in Table 5, among AD patients on Sorok Island, the decline in age at death was significant beginning in 2008, when the war on dementia was declared in 2012, when the DMA were enacted, but the 5-year declining trend from 2015 clearly differed from that in 2005. The group taking both dementia and psychotropic drugs has declined over more than 20 years. However, the life expectancy of Koreans has steadily increased. The Kolmogorov‒Smirnov test did not significantly differ among the three groups. The Friedman test for repeated measures provides 99.9% confidence differences between the ages of the groups being measured. AADs are associated with a gradual decrease in life expectancy. (Table S6) Excess acetylcholine affects acetylcholine receptor gene expression in the EDI code-based cohort-based RCT study on Sorok Island18. The AA equation for excess acetylcholine was shown to be significantly negatively related to the prevalence of bronchitis and chronic obstructive pulmonary disease (COPD) from 2011 to 2015 on Sorok Island18. A noticeable decrease in age at death was observed beginning in 2015 in the first group1, as shown in Table 5.
| year | AD First group1 | AD First & Second group2 | The life expectancy of Korean |
|---|---|---|---|
| 2005 | 90.4 | 93.98 | 78.24 |
| 2006 | 82.5 | 93.49 | 78.78 |
| 2007 | 92.38 | 92.2 | 79.16 |
| 2008 | 96.25 | 92.87 | 79.6 |
| 2009 | 94.74 | 93.09 | 80.04 |
| 2010 | 92.14 | 90.24 | 80.24 |
| 2011 | 91.25 | 90.22 | 80.62 |
| 2012 | 90.16 | 89.28 | 80.87 |
| 2013 | 90.6 | 89.07 | 81.36 |
| 2014 | 92.27 | 90.94 | 81.8 |
| 2015 | 85.56 | 84.88 | 82.06 |
| 2016 | 87.22 | 87.88 | 82.4 |
| 2017 | 88.45 | 86.67 | 82.7 |
| 2018 | 88.2 | 72.1 | 82.7 |
| 2019 | 88.2 | 72.1 | 83.3 |
| Sum | 1350 | 1319 | 1213.87 |
| Mean | 90 | 88 | 81 |
| SD | 4 | 7 | 2 |
| 95% CI | 0 | 0 | 0 |
| ( | 90 | 88 | 81 |
| ) | 90 | 88 | 81 |
| 3p-value | 0.97266 | 0.33047 | 0.96806 |
| 4Kolmogorov-Smirnov Test (D) | 0.11635 | 0.23407 | 0.11840 |
| 5Skewness Kurtosis Normality | -0.325353 0.448167 significantly from that which is normally distributed. | -1.782821 2.432097 significantly from that which is normally distributed. | -0.172428 -1.120456 significantly from that which is normally distributed. |
| 6The Friedman Test between three groups | The X2r statistic is 20.9333 (2, N = 15). The p value is .00003. The result is significant at p < .01. | ||
| 1First Group: Group with symptomatic Relief of Alzheimer’s Disease (Table S2); 2Second Group: Group with both symptomatic and psychological relief of Alzheimer’s Disease (Table S2 & Table S3). 3The p value quantifies this probability, with a low probability indicating that the sample diverges from a normal distribution to an extent unlikely to arise merely by chance. 4The test statistic (D) provides a measurement of the divergence of the sample distribution from the normal distribution. The higher the value of D is, the less probable it is that your data are normally distributed. 5The nearer both these are to zero, the more likely it is that your distribution is normal. 6The Friedman test is the nonparametric alternative to one-way ANOVA with repeated measures. | |||
Limitations of our study
Currently, the quarterly sales of AD drugs between 2009 and 2019 decreased by 86% over the ten years in France, decreased by 15% in Spain, remained stable in Germany, and increased by 107% in the UK 19. It is challenging to manage adverse effects from AADs 16 20. We updated the information on AD prescriptions, including information about the pandemic era. This study included a large sample size, long period, and large data-based rigorous information retrieval. Nonetheless, only the increase or decrease in the number of deaths was monitored. As always in science, the more data we have, the better conclusions we can draw and act accordingly.
These data analyses might be possible because Korean public health centers have been monitoring and encouraging consistent use of AADs 21. The Korean government announced AD drugs as AD treatments that should be taken consistently over one year 1.
SSRIs have anti-inflammatory effects.
SSRIs have anti-inflammatory effects through serotonin transporter inhibition and a reduced risk for a severe clinical course during the pandemic 22 23. Sertraline, fluoxetine, escitalopram, and fluvoxamine attenuate inflammation in injured striatal neurons by increasing anti-inflammatory cytokines and can control inflammatory neurons 24. SSRI treatment does not increase the risk of suicidal behavior in either youths or adults 25. Aripiprazole has been prescribed for combination treatment of vascular dementia because of its synergistic neuroprotective effects 26 27. Continued observation and clinical trials are required for their effects on depression, obsessive compulsory disorder, suicide, anti-inflammation, and anxiety disorders 28 29 30 31.
Therefore, South Korea should use AADs carefully.
Donepezil was associated with no evidence of delaying the onset of AD or MCI. The commonly regarded benefits are minor, short lived and associated with significant side effects 32. However, the findings of the present study suggested that the number of deaths caused by galantamine differed.
Antipsychotic prescriptions for an antipsychotic (haloperidol, olanzapine, quetiapine, or risperidone), valproic acid or its derivatives, or an antidepressant in older adults with dementia are associated with increased mortality 4. Haloperidol has been used to treat aggression (not agitation) in patients with dementia and improve behavioral symptoms, and it has improved the global clinical impression of change 33. Excessive motor activity and unwarranted accusations respond preferentially to haloperidol 34. We requested the disclosure of information on the status of drug side effects of AADs, but they did not have relevant information. Antipsychotic drug use for dementia-related behavioral disorders increases mortality 35.
This study investigated the benefits, hazards, and sustainability of AADs. Deaths and AADs based on NHIS big data could be useful for safe dementia care.
Ethical Approval
The National Agency approved this study for the management of life-sustaining treatment, which certified that the life-sustaining treatments were managed properly (Korea National Institute for Bioethics Policy (KoNIBP) approval number P01-202007-22-006). All protocols were carried out in accordance with the Declaration of Helsinki. This study in the analyses was conducted legally in accordance with South Korea's Official Information Disclosure Act. The participants were educated about the purpose of the study, and participants gave their signed written informed consent letters.
Consent for publication.
Not applicable.
Funding
No funding
Availability of data and materials
All the data are available in the main text or the supplementary materials. Additional data supporting this study’s findings are available from the corresponding author upon reasonable request. Additional basic data are provided at the Center for Open Science (Lee J. Death Toll by Dementia Drug [Internet]). OSF; 2021. Available from: osf.io/z7ph2).
Corresponding Author: Jong Hoon Lee, MD, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu Seoul (03080), South Korea
Author Contributions: Dr. Lee had full access to all of the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.
Concept and design: J.L.
Acquisition, analysis, or interpretation of the data: J.L.
Drafting of the manuscript: J.L.
Critical revision of the manuscript for important intellectual content: J.L.
Statistical analysis: J.L.
Administrative, technical, or material support: J.L.
Supervision: J.L.
Conflicts of interest disclosure: The author has no conflicts of interest to declare.
Code availability.
Not applicable.
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No competing interests reported.