# Effectiveness and Safety of the Korean Medicine Senior Health Promotion Program Using Herbal Medicine and Acupuncture for Mild Cognitive Impairment: A Retrospective Study of 500 Patients in Seoul, Korea

Authors: Hyo-Weon Suh; Jae-Hyun Seol; Eun-Joo Bae; Hui-Yong Kwak; Sunggyu Hong; Yong-Sin Park; Jae Hwan Lim; Sun-Yong Chung
Journal: Evidence-Based Complementary and Alternative Medicine
 (2021)

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## Abstract

Background. The management of mild cognitive impairment (MCI) is becoming increasingly important. The Korean Medicine Senior Health Promotion Program (KSHPP) was developed in 2016, and it has been in use to date. This study aimed to assess the effectiveness of KSHPP using herbal medicine and acupuncture for treating MCI and the safety of herbal medicine using liver and renal function tests. Methods. We retrospectively reviewed the medical records of the participants with MCI. We assessed the Korean version of the Montreal Cognitive Assessment (MoCA-K), the Mini-Mental State Examination-Dementia Screening (MMSE-DS), and the Geriatric Depression Scale Short Form-Korea version (GDSSF-K) scores before and after KSHPP to determine its effectiveness. To evaluate its safety, the liver and renal function tests were conducted before and after herbal treatment. Results. We enrolled 1002 participants, and 500 participants satisfied the inclusion criteria. Of 500 patients, 364 (72.8%) were depressed and 136 (27.2%) were not. The mean MoCA-K score significantly increased by 2.77 for the entire sample and 3.22 for the depressed sample (all P<0.0001). The mean MMSE-DS score significantly increased by 2.19 for the entire sample and 2.51 for the depressed sample (all P<0.0001); the mean GDSSF-K score significantly decreased by 1.73 for the entire sample and 2.68 for the depressed sample (all P<0.0001). Conclusions. Our findings suggest that Korean medicine interventions can improve cognitive function and depression symptoms in patients with MCI. In addition, the results of the liver and renal function tests were analyzed as surrogate outcomes to assess the safety of herbal medicine. Based on these results, we expect that Korean medicine interventions can promote the cognitive and mental health of seniors. However, as there were several study limitations, particularly study design, practice effect, and short follow-up, these results must be interpreted with caution. We need a further long-term study with a rigorous design to retain confidence in the effectiveness and safety of KSHPP.


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## Body

## 1. Introduction

The global action plan on the public health response to dementia 2017–2025 was adopted by the World Health Organization (WHO) member states in 2017 [1]. Dementia is attracting attention globally because its burden on patients and caregivers is high. Although the currently available medications for dementia can delay its progression, they cannot provide complete recovery of patients to their previous states. Thus, the prevention and early detection of mild cognitive impairment (MCI) are becoming increasingly important.MCI, an intermediate stage between normal aging and dementia, is well known as a risk factor for dementia. The annualized rates of conversion from MCI to dementia have been reported between 7.5% and 16.5% [2]. Unfortunately, despite the importance of MCI management, the therapeutic options are limited. The 2017 American Academy of Neurology (AAN) guideline only recommended regular exercise and cognitive training for patients with MCI [3]. Cholinesterase inhibitors, usually indicated for dementia, are not recommended for MCI because they are associated with more gastrointestinal adverse effects than clinically beneficial effects [4, 5].In contrast to the limitations of conventional treatment, previous systematic reviews have shown that herbal medicine is effective and safe for MCI [6, 7], and acupuncture is effective for vascular cognitive impairment with no dementia [8, 9] and amnestic MCI [10, 11].In Korea, herbal medicine and acupuncture have been widely used. This may be due to the Korean medical system, not just cultural impact. According to the Medical Service Act, Korean licensed healthcare providers include doctors, Korean medicine doctors, dentists, nurses, and midwives. Korean medicine doctors must obtain a license from the Minister of Health and Welfare after graduating from a college or professional graduate school of Korean medicine and pass the Korea Health Personnel Licensing Examination. As there is a specialist system, a general practitioner of Korean medicine can become a specialist by completing a 1-year internship and 3-year residency. The qualifications of Korean medicine doctors are strictly managed and institutionalized.In terms of community, Korean medicine associations were established in each region, and some Korean medicine doctors have engaged in public healthcare at public health centers. Based on these fundamental resources, several local governments have implemented various public health promotion programs using Korean medicine. Since 2016, the Korean Medicine Senior Health Promotion Program (KSHPP) has been implemented by the Seoul Metropolitan Government and the Seoul Korean Medicine Association in several districts of Seoul, Korea. The KSHPP aims to prevent and manage cognitive impairment and geriatric depression in community-dwelling older adults within public health centers and Korean medicine clinics. In this study, we retrospectively reviewed the medical records of patients with mild cognitive impairment who received herbal medicine and acupuncture at Korean medicine clinic (KMC) as part of KSHPP. This study aimed to assess the effectiveness of KSHPP involving herbal medicine and acupuncture for MCI and the safety of herbal medicine based on liver and renal function tests.


## 2. Materials and Methods

### 2.1. Study Design

We retrospectively reviewed the medical records of the participants who participated in KSHPP from multiple Korean medicine clinics in 2019. Informed consent had been obtained from all the participants at the beginning of the program. This retrospective study was approved by the Institutional Review Board of the Kyung Hee University (KHSIRB-19-393).


### 2.2. Overview of the KSHPP

Senior citizens, aged 60 or more, who voluntarily signed the informed consent form could participate in KSHPP. Eligibility was assessed using the Mini-Mental State Examination-Dementia Screening (MMSE-DS) and Geriatric Depression Scale Short Form-Korea version (GDSSF-K) in public health centers and Korean medicine clinics. The Korean version of the Montreal Cognitive Assessment (MoCA-K) was additionally used in Korean medicine clinics by doctors of Korean medicine. The participants who scored within the limits of the normal population when assessed with MMSE-DS and GDSSF-K were assigned to a public health center, where they would participate in group sessions mainly consisting of education, group activity, and acupuncture. Four public health centers participated in KSHPP. On the other hand, the participants who exceeded the cutoff scores for any of the screening tools for cognitive impairment and depression (i.e., MMSE-DS, MoCA-K, and GDSSF-K) were allocated to KMC. However, those diagnosed with dementia or high suicide risks were excluded. One hundred and twenty-eight KMCs participated in KSHPP, providing herbal medicine and acupuncture to the participants. The doctors of Korean medicine who worked at the clinics voluntarily participated in this program. They are all licensed Korean medicine doctors, and their qualifications are not restricted by their expertise or experience in Korean medicine. The Korean Medicine Association educated them on standard protocols.


### 2.3. Participants

In this study, we identified MCI patients based on the MoCA-K score. The inclusion criteria were as follows: older adults who participated in KSHPP and were allocated to KMC in 2019; the availability of MoCA-K, MMSE-DS, and GDSSF-K scores before and after the program; and a MoCA-K score of <23.The exclusion criterion was missing information from the chart on the types of interventions (i.e., a combination of herbal decoction and acupuncture, a combination of herbal extract and acupuncture, and acupuncture monotherapy) because subgroup analysis would be conducted according to the types of interventions.


### 2.4. Interventions

During KSHPP, the participants allocated to KMCs were individually managed.


#### 2.4.1. Acupuncture

The protocol of acupuncture was standardized. Treatment acupoints were GV20, EX-HN1, LI4, LR3, ST36, HT7, and PC6. The duration of acupuncture was 25 minutes. The recommended number of acupuncture sessions was 12–20 (twice a week).


#### 2.4.2. Herbal Medicine

Five herbal medicine formulas were designed based on evidence from previous studies and the clinical experiences of the authors (YSP, JHL, and SYC) (Table1). Two of the authors (YSP and JHL) were representatives of the Seoul Korean Medicine Association, and the other (SYC) was a professor at the College of Korean Medicine, Kyung Hee University. The authors (YSP, JHL, and SYC) were licensed Korean medicine doctors with PhDs and an average of 23 years of experience (range 21–27 years) at the study’s initiation. Among them, two authors (JHK and SYC) were Korean medicine neuropsychiatrists.Table 1
Details of herbal medicine treatments.
Herbal formulaIngredientsGuibi-tangAngelicae Gigantis Radix, Longanae Arillus, Zizyphi Semen, Polygalae Radix, Ginseng Radix, Astragali Radix, Atractylodis Rhizoma, and Alba Poria Sclertum cum Pini Radix 3.75 g, respectively. Aucklandiae Radix 1.88 g. Glycyrrhizae Radix et Rhizoma 1.13 g. Zingiberis Rhizoma Crudus 6.25 g. Zizyphi Fructus 3.75 g.Modified Guibi-tangAngelicae Gigantis Radix, Longanae Arillus, Zizyphi Semen, Polygalae Radix, Ginseng Radix, Astragali Radix, Atractylodis Rhizoma, and Alba Poria Sclertum cum Pini Radix 3.75 g, respectively. Aucklandiae Radix 1.88 g. Glycyrrhizae Radix et Rhizoma 1.13 g. Zingiberis Rhizoma Crudus 6.25 g. Zizyphi Fructus 3.75 g. Moutan Cortex Radicis, Bupleuri Radix, and Gardeniae Fructus 3.75 g, respectively.Cheonwangbosim-danRehmanniae Radix Crudus 15 g. Coptidis Rhizoma Preparata cum Vinum7.5 g. Acori Gramineri Rhizoma, Ginseng Radix, Angelicae Gigantis Radix, Schisandrae Fructus, Asparagi Tuber, Thujae Semen, Zizyphi Semen, Scrophulariae Radix, Salviae Miltiorrhizae Radix, Polygalae Radix, Poria Sclertum cum Pini Radix, Liriopis tuber, and Castaneae Semen 1.88 g, respectively.Jowiseungcheong-tangCoicis Semen and Castaneae Semen 8 g, respectively. Raphani Semen and Longanae Arillus 6 g, respectively. Liriopis tuber, Platycodonis Radix, Acori Gramineri Rhizoma, Thujae Semen, Zizyphi Semen, and Massa Medicata Fermentata 4 g, respectively. Ephedrae Herba, Schisandrae Fructus, Amomi Fructus, and Polygalae Radix 3 g, respectively∗Due to different formula, herbal extract was unusable.Hwangnyeonhaedok-tangCoptidis Rhizoma, Scutellariae Radix, Phellodendri Cortex, and Gardeniae Fructus 4.69 g, respectively.During KSHPP, 128 Korean medicine doctors and practitioners in the community chose one of five formulas based on their judgment (i.e., pattern identification). However, our standard protocol did not provide specific criteria to practitioners.Guibi-tang and modified Guibi-tang tonify qi and replenish blood. According to the results of a randomized trial, the MMSE score of patients with Alzheimer's disease (AD) increased after taking Guibi-tang for 3 months, in contrast with those of the other control groups [12]. A more recent crossover study also showed the add-on effect of Guibi-tang compared with monotherapy with acetylcholinesterase inhibitors for 2 months [13]. Chenwangbosim-dan enriches yin and nourishes blood. Preclinical studies [14, 15] and an observational study using a nationwide database in Taiwan showed that Chenwangbosim-dan was frequently used for dementia patients in Taiwan [16]. However, this is yet to be investigated through clinical trials. Jowiseungcheong-tang is a unique formula only used in Korea, and it is recommended as a representative prescription for AD in textbooks of Korean medicine [17] and prescribed frequently by doctors of Korean medicine to manage dementia [18]. According to previous studies, AD patients taking Jowiseungcheong-tang for 6–9 months maintained the baseline total score on the dementia rating scale after treatment [19, 20]. Hwangnyeonhaedok-tang clears heat and detoxifies. In a randomized controlled trial, patients with AD were administered almitrine or a combination of herbal medicines (i.e., Hwangnyeonhaedok-tang and Sagunja-tang) for 60 days, and the effective rate of the herbal medicine group was significantly higher than that of the almitrine group [21].Herbal medicine could be prescribed as herbal decoction or herbal extract. In the case of herbal decoction, the doctors of Korean medicine prescribed one herbal formula out of five (Guibi-tang, modified Guibi-tang, Cheonwangbosim-dan, Jowiseungcheong-tang, and Hwangnyeonhaedok-tang) for up to 15 days during acupuncture sessions. In the case of herbal extract, the doctors prescribed the herbal formula out of four (Guibi-tang, modified Guibi-tang, Cheonwangbosim-dan, and Hwangnyeonhaedok-tang) for up to 3 times, 20 days at a time, during acupuncture sessions. The formula could be changed at any time. Because KSHPP was a public health service supported by the Seoul Metropolitan Government, the duration of treatment was limited by the policy of the Seoul Metropolitan Government.


### 2.5. Outcome Measurements

To observe the effectiveness of KSHPP using herbal medicine and acupuncture, we assessed the prepost changes in the MoCA-K, MMSE-DS, and GDSSF-K scores. All the outcomes were measured after the acupuncture. High scores of MoCA-K and MMSE-DS represent improvements in cognition, whereas low scores of GDSSF-K represent an improvement in geriatric depression. In this study, we denoted MCI by MoCA-K of <23 and depression by a GDSSF-K score of >4.MoCA is a more suitable screening tool for MCI than the MMSE in older adults [22]. Its cutoff score was 26 in the original version [23], but currently, a cutoff score of 23 is suggested for better diagnostic accuracy [24, 25]. It consists of the trail-making test-B, three-dimensional cube copy, clock drawing test, confrontation naming task, short-term memory recall task, digit span test, serial 7s, repetition of sentences, semantic verbal fluency task, and the verbal abstraction task. In addition, the orientation of time and place was also evaluated. The Korean version of MoCA has been validated in the clinical setting, and a cutoff score of 23 has been adopted [26].The Korean version of the MMSE-DS was developed to improve the limitations of the existing MMSE and better reflect the demographic and cultural characteristics of older adults in Korea [27]. It consists of 19 questions for evaluating each area of cognitive function. The optimal cutoff point of MMSE-DS for dementia was 21/22, and the diagnostic sensitivity and specificity were 0.818 and 0.805, respectively. However, as the test results appeared to be significantly influenced by age and the level of education, the normative data were estimated according to gender, age, and the education level. If the score fell below 1.5 standard deviations compared to the normal score, dementia was suspected, and a further diagnostic test was requested.The GDSSF-K is a scale for evaluating the depressive symptoms of older adults. This scale distinguishes between the symptoms caused by increasing age and those caused by depression, and it consists of simple and easily understandable questions for older adults. The previously developed 30-item binary scale [28] has been simplified to include 15 items [29], and Ki Baek-seok has adapted and validated it in Korea [30]; five items are scored as depressed when their responses are affirmative, and 10 items are scored as depressed when their responses are not affirmative. When 5 points were used as a cutoff, sensitivity was 42.3% and specificity was 88.7%.


### 2.6. Safety

Liver function tests (LFTs), including aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin (TB), direct bilirubin (DB), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT), and renal function tests (RFTs), including blood urea nitrogen (BUN) and creatinine, were performed before and after herbal treatment to evaluate safety.We analyzed the changes in all the biochemical values and identified the potentially relevant cases of liver injury or renal dysfunction. The normal ranges are 0–40 IU/L for AST and ALT, 0.3–1.2 mg/dL for TB, 0–0.4 mg/dL for DB, 30–120 IU/L for ALP, 9–64 IU/L for GGT, 8–20 mg/dL for BUN, and 0.7–1.2 mg/dL for creatinine.Liver injury was defined as an increase of over 5 × the upper limit of normal (ULN) ALT (ULNALT) and/or an increase of over 2 × the ULN ALP (ULNALP) according to the updated Roussel Uclaf causality assessment method [31]. We also categorized the reaction types using the R ratio: R ratio = (ALT/ULNALT)/(ALP/ULNALP). Liver injury was categorized as follows: hepatocellular: R > 5 and ALT >2 × ULNALT; cholestatic: R < 2 and ALP >2 × ULNALP; mixed: 2 < R < 5, and both ALT, ALP >2 × ULN. Drug-induced liver injury (DILI) may be hepatocellular or mixed.The criteria for suspected kidney disease for screening tests defined by the Ministry of Health and Welfare of Korea are as follows: level of creatinine is greater than 1.5 mg/dL and (b) estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease equation is lower than 60 mL/min/1.73 m2. The Modification of Diet in Renal Disease equation is as follows: 186 × (creatinine/88.4)−1.154 × (age)−0.203 × (0.742 if female) × (1.210 if black).


### 2.7. Statistical Analysis

The statistical analyses were performed using SAS® version 9.4 (SAS Institute, Inc.). The demographic characteristics of the participants presented are based on descriptive analyses. Continuous data are presented as mean ± SD, and they were analyzed using the independent two-samplet-test or the Wilcoxon signed-rank test for two groups and analysis for variance (ANOVA) for more than two groups. Binary data are presented as number (%), and they were analyzed using the chi-squared or Fisher’s exact test. All the tests were two-sided, and a P value of <0.05 was considered statistically significant. The effect size was reported by Cohen’s d.


## 2.1. Study Design

We retrospectively reviewed the medical records of the participants who participated in KSHPP from multiple Korean medicine clinics in 2019. Informed consent had been obtained from all the participants at the beginning of the program. This retrospective study was approved by the Institutional Review Board of the Kyung Hee University (KHSIRB-19-393).


## 2.2. Overview of the KSHPP

Senior citizens, aged 60 or more, who voluntarily signed the informed consent form could participate in KSHPP. Eligibility was assessed using the Mini-Mental State Examination-Dementia Screening (MMSE-DS) and Geriatric Depression Scale Short Form-Korea version (GDSSF-K) in public health centers and Korean medicine clinics. The Korean version of the Montreal Cognitive Assessment (MoCA-K) was additionally used in Korean medicine clinics by doctors of Korean medicine. The participants who scored within the limits of the normal population when assessed with MMSE-DS and GDSSF-K were assigned to a public health center, where they would participate in group sessions mainly consisting of education, group activity, and acupuncture. Four public health centers participated in KSHPP. On the other hand, the participants who exceeded the cutoff scores for any of the screening tools for cognitive impairment and depression (i.e., MMSE-DS, MoCA-K, and GDSSF-K) were allocated to KMC. However, those diagnosed with dementia or high suicide risks were excluded. One hundred and twenty-eight KMCs participated in KSHPP, providing herbal medicine and acupuncture to the participants. The doctors of Korean medicine who worked at the clinics voluntarily participated in this program. They are all licensed Korean medicine doctors, and their qualifications are not restricted by their expertise or experience in Korean medicine. The Korean Medicine Association educated them on standard protocols.


## 2.3. Participants

In this study, we identified MCI patients based on the MoCA-K score. The inclusion criteria were as follows: older adults who participated in KSHPP and were allocated to KMC in 2019; the availability of MoCA-K, MMSE-DS, and GDSSF-K scores before and after the program; and a MoCA-K score of <23.The exclusion criterion was missing information from the chart on the types of interventions (i.e., a combination of herbal decoction and acupuncture, a combination of herbal extract and acupuncture, and acupuncture monotherapy) because subgroup analysis would be conducted according to the types of interventions.


## 2.4. Interventions

During KSHPP, the participants allocated to KMCs were individually managed.


### 2.4.1. Acupuncture

The protocol of acupuncture was standardized. Treatment acupoints were GV20, EX-HN1, LI4, LR3, ST36, HT7, and PC6. The duration of acupuncture was 25 minutes. The recommended number of acupuncture sessions was 12–20 (twice a week).


### 2.4.2. Herbal Medicine

Five herbal medicine formulas were designed based on evidence from previous studies and the clinical experiences of the authors (YSP, JHL, and SYC) (Table1). Two of the authors (YSP and JHL) were representatives of the Seoul Korean Medicine Association, and the other (SYC) was a professor at the College of Korean Medicine, Kyung Hee University. The authors (YSP, JHL, and SYC) were licensed Korean medicine doctors with PhDs and an average of 23 years of experience (range 21–27 years) at the study’s initiation. Among them, two authors (JHK and SYC) were Korean medicine neuropsychiatrists.Table 1
Details of herbal medicine treatments.
Herbal formulaIngredientsGuibi-tangAngelicae Gigantis Radix, Longanae Arillus, Zizyphi Semen, Polygalae Radix, Ginseng Radix, Astragali Radix, Atractylodis Rhizoma, and Alba Poria Sclertum cum Pini Radix 3.75 g, respectively. Aucklandiae Radix 1.88 g. Glycyrrhizae Radix et Rhizoma 1.13 g. Zingiberis Rhizoma Crudus 6.25 g. Zizyphi Fructus 3.75 g.Modified Guibi-tangAngelicae Gigantis Radix, Longanae Arillus, Zizyphi Semen, Polygalae Radix, Ginseng Radix, Astragali Radix, Atractylodis Rhizoma, and Alba Poria Sclertum cum Pini Radix 3.75 g, respectively. Aucklandiae Radix 1.88 g. Glycyrrhizae Radix et Rhizoma 1.13 g. Zingiberis Rhizoma Crudus 6.25 g. Zizyphi Fructus 3.75 g. Moutan Cortex Radicis, Bupleuri Radix, and Gardeniae Fructus 3.75 g, respectively.Cheonwangbosim-danRehmanniae Radix Crudus 15 g. Coptidis Rhizoma Preparata cum Vinum7.5 g. Acori Gramineri Rhizoma, Ginseng Radix, Angelicae Gigantis Radix, Schisandrae Fructus, Asparagi Tuber, Thujae Semen, Zizyphi Semen, Scrophulariae Radix, Salviae Miltiorrhizae Radix, Polygalae Radix, Poria Sclertum cum Pini Radix, Liriopis tuber, and Castaneae Semen 1.88 g, respectively.Jowiseungcheong-tangCoicis Semen and Castaneae Semen 8 g, respectively. Raphani Semen and Longanae Arillus 6 g, respectively. Liriopis tuber, Platycodonis Radix, Acori Gramineri Rhizoma, Thujae Semen, Zizyphi Semen, and Massa Medicata Fermentata 4 g, respectively. Ephedrae Herba, Schisandrae Fructus, Amomi Fructus, and Polygalae Radix 3 g, respectively∗Due to different formula, herbal extract was unusable.Hwangnyeonhaedok-tangCoptidis Rhizoma, Scutellariae Radix, Phellodendri Cortex, and Gardeniae Fructus 4.69 g, respectively.During KSHPP, 128 Korean medicine doctors and practitioners in the community chose one of five formulas based on their judgment (i.e., pattern identification). However, our standard protocol did not provide specific criteria to practitioners.Guibi-tang and modified Guibi-tang tonify qi and replenish blood. According to the results of a randomized trial, the MMSE score of patients with Alzheimer's disease (AD) increased after taking Guibi-tang for 3 months, in contrast with those of the other control groups [12]. A more recent crossover study also showed the add-on effect of Guibi-tang compared with monotherapy with acetylcholinesterase inhibitors for 2 months [13]. Chenwangbosim-dan enriches yin and nourishes blood. Preclinical studies [14, 15] and an observational study using a nationwide database in Taiwan showed that Chenwangbosim-dan was frequently used for dementia patients in Taiwan [16]. However, this is yet to be investigated through clinical trials. Jowiseungcheong-tang is a unique formula only used in Korea, and it is recommended as a representative prescription for AD in textbooks of Korean medicine [17] and prescribed frequently by doctors of Korean medicine to manage dementia [18]. According to previous studies, AD patients taking Jowiseungcheong-tang for 6–9 months maintained the baseline total score on the dementia rating scale after treatment [19, 20]. Hwangnyeonhaedok-tang clears heat and detoxifies. In a randomized controlled trial, patients with AD were administered almitrine or a combination of herbal medicines (i.e., Hwangnyeonhaedok-tang and Sagunja-tang) for 60 days, and the effective rate of the herbal medicine group was significantly higher than that of the almitrine group [21].Herbal medicine could be prescribed as herbal decoction or herbal extract. In the case of herbal decoction, the doctors of Korean medicine prescribed one herbal formula out of five (Guibi-tang, modified Guibi-tang, Cheonwangbosim-dan, Jowiseungcheong-tang, and Hwangnyeonhaedok-tang) for up to 15 days during acupuncture sessions. In the case of herbal extract, the doctors prescribed the herbal formula out of four (Guibi-tang, modified Guibi-tang, Cheonwangbosim-dan, and Hwangnyeonhaedok-tang) for up to 3 times, 20 days at a time, during acupuncture sessions. The formula could be changed at any time. Because KSHPP was a public health service supported by the Seoul Metropolitan Government, the duration of treatment was limited by the policy of the Seoul Metropolitan Government.


## 2.4.1. Acupuncture

The protocol of acupuncture was standardized. Treatment acupoints were GV20, EX-HN1, LI4, LR3, ST36, HT7, and PC6. The duration of acupuncture was 25 minutes. The recommended number of acupuncture sessions was 12–20 (twice a week).


## 2.4.2. Herbal Medicine

Five herbal medicine formulas were designed based on evidence from previous studies and the clinical experiences of the authors (YSP, JHL, and SYC) (Table1). Two of the authors (YSP and JHL) were representatives of the Seoul Korean Medicine Association, and the other (SYC) was a professor at the College of Korean Medicine, Kyung Hee University. The authors (YSP, JHL, and SYC) were licensed Korean medicine doctors with PhDs and an average of 23 years of experience (range 21–27 years) at the study’s initiation. Among them, two authors (JHK and SYC) were Korean medicine neuropsychiatrists.Table 1
Details of herbal medicine treatments.
Herbal formulaIngredientsGuibi-tangAngelicae Gigantis Radix, Longanae Arillus, Zizyphi Semen, Polygalae Radix, Ginseng Radix, Astragali Radix, Atractylodis Rhizoma, and Alba Poria Sclertum cum Pini Radix 3.75 g, respectively. Aucklandiae Radix 1.88 g. Glycyrrhizae Radix et Rhizoma 1.13 g. Zingiberis Rhizoma Crudus 6.25 g. Zizyphi Fructus 3.75 g.Modified Guibi-tangAngelicae Gigantis Radix, Longanae Arillus, Zizyphi Semen, Polygalae Radix, Ginseng Radix, Astragali Radix, Atractylodis Rhizoma, and Alba Poria Sclertum cum Pini Radix 3.75 g, respectively. Aucklandiae Radix 1.88 g. Glycyrrhizae Radix et Rhizoma 1.13 g. Zingiberis Rhizoma Crudus 6.25 g. Zizyphi Fructus 3.75 g. Moutan Cortex Radicis, Bupleuri Radix, and Gardeniae Fructus 3.75 g, respectively.Cheonwangbosim-danRehmanniae Radix Crudus 15 g. Coptidis Rhizoma Preparata cum Vinum7.5 g. Acori Gramineri Rhizoma, Ginseng Radix, Angelicae Gigantis Radix, Schisandrae Fructus, Asparagi Tuber, Thujae Semen, Zizyphi Semen, Scrophulariae Radix, Salviae Miltiorrhizae Radix, Polygalae Radix, Poria Sclertum cum Pini Radix, Liriopis tuber, and Castaneae Semen 1.88 g, respectively.Jowiseungcheong-tangCoicis Semen and Castaneae Semen 8 g, respectively. Raphani Semen and Longanae Arillus 6 g, respectively. Liriopis tuber, Platycodonis Radix, Acori Gramineri Rhizoma, Thujae Semen, Zizyphi Semen, and Massa Medicata Fermentata 4 g, respectively. Ephedrae Herba, Schisandrae Fructus, Amomi Fructus, and Polygalae Radix 3 g, respectively∗Due to different formula, herbal extract was unusable.Hwangnyeonhaedok-tangCoptidis Rhizoma, Scutellariae Radix, Phellodendri Cortex, and Gardeniae Fructus 4.69 g, respectively.During KSHPP, 128 Korean medicine doctors and practitioners in the community chose one of five formulas based on their judgment (i.e., pattern identification). However, our standard protocol did not provide specific criteria to practitioners.Guibi-tang and modified Guibi-tang tonify qi and replenish blood. According to the results of a randomized trial, the MMSE score of patients with Alzheimer's disease (AD) increased after taking Guibi-tang for 3 months, in contrast with those of the other control groups [12]. A more recent crossover study also showed the add-on effect of Guibi-tang compared with monotherapy with acetylcholinesterase inhibitors for 2 months [13]. Chenwangbosim-dan enriches yin and nourishes blood. Preclinical studies [14, 15] and an observational study using a nationwide database in Taiwan showed that Chenwangbosim-dan was frequently used for dementia patients in Taiwan [16]. However, this is yet to be investigated through clinical trials. Jowiseungcheong-tang is a unique formula only used in Korea, and it is recommended as a representative prescription for AD in textbooks of Korean medicine [17] and prescribed frequently by doctors of Korean medicine to manage dementia [18]. According to previous studies, AD patients taking Jowiseungcheong-tang for 6–9 months maintained the baseline total score on the dementia rating scale after treatment [19, 20]. Hwangnyeonhaedok-tang clears heat and detoxifies. In a randomized controlled trial, patients with AD were administered almitrine or a combination of herbal medicines (i.e., Hwangnyeonhaedok-tang and Sagunja-tang) for 60 days, and the effective rate of the herbal medicine group was significantly higher than that of the almitrine group [21].Herbal medicine could be prescribed as herbal decoction or herbal extract. In the case of herbal decoction, the doctors of Korean medicine prescribed one herbal formula out of five (Guibi-tang, modified Guibi-tang, Cheonwangbosim-dan, Jowiseungcheong-tang, and Hwangnyeonhaedok-tang) for up to 15 days during acupuncture sessions. In the case of herbal extract, the doctors prescribed the herbal formula out of four (Guibi-tang, modified Guibi-tang, Cheonwangbosim-dan, and Hwangnyeonhaedok-tang) for up to 3 times, 20 days at a time, during acupuncture sessions. The formula could be changed at any time. Because KSHPP was a public health service supported by the Seoul Metropolitan Government, the duration of treatment was limited by the policy of the Seoul Metropolitan Government.


## 2.5. Outcome Measurements

To observe the effectiveness of KSHPP using herbal medicine and acupuncture, we assessed the prepost changes in the MoCA-K, MMSE-DS, and GDSSF-K scores. All the outcomes were measured after the acupuncture. High scores of MoCA-K and MMSE-DS represent improvements in cognition, whereas low scores of GDSSF-K represent an improvement in geriatric depression. In this study, we denoted MCI by MoCA-K of <23 and depression by a GDSSF-K score of >4.MoCA is a more suitable screening tool for MCI than the MMSE in older adults [22]. Its cutoff score was 26 in the original version [23], but currently, a cutoff score of 23 is suggested for better diagnostic accuracy [24, 25]. It consists of the trail-making test-B, three-dimensional cube copy, clock drawing test, confrontation naming task, short-term memory recall task, digit span test, serial 7s, repetition of sentences, semantic verbal fluency task, and the verbal abstraction task. In addition, the orientation of time and place was also evaluated. The Korean version of MoCA has been validated in the clinical setting, and a cutoff score of 23 has been adopted [26].The Korean version of the MMSE-DS was developed to improve the limitations of the existing MMSE and better reflect the demographic and cultural characteristics of older adults in Korea [27]. It consists of 19 questions for evaluating each area of cognitive function. The optimal cutoff point of MMSE-DS for dementia was 21/22, and the diagnostic sensitivity and specificity were 0.818 and 0.805, respectively. However, as the test results appeared to be significantly influenced by age and the level of education, the normative data were estimated according to gender, age, and the education level. If the score fell below 1.5 standard deviations compared to the normal score, dementia was suspected, and a further diagnostic test was requested.The GDSSF-K is a scale for evaluating the depressive symptoms of older adults. This scale distinguishes between the symptoms caused by increasing age and those caused by depression, and it consists of simple and easily understandable questions for older adults. The previously developed 30-item binary scale [28] has been simplified to include 15 items [29], and Ki Baek-seok has adapted and validated it in Korea [30]; five items are scored as depressed when their responses are affirmative, and 10 items are scored as depressed when their responses are not affirmative. When 5 points were used as a cutoff, sensitivity was 42.3% and specificity was 88.7%.


## 2.6. Safety

Liver function tests (LFTs), including aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin (TB), direct bilirubin (DB), alkaline phosphatase (ALP), and gamma-glutamyl transpeptidase (GGT), and renal function tests (RFTs), including blood urea nitrogen (BUN) and creatinine, were performed before and after herbal treatment to evaluate safety.We analyzed the changes in all the biochemical values and identified the potentially relevant cases of liver injury or renal dysfunction. The normal ranges are 0–40 IU/L for AST and ALT, 0.3–1.2 mg/dL for TB, 0–0.4 mg/dL for DB, 30–120 IU/L for ALP, 9–64 IU/L for GGT, 8–20 mg/dL for BUN, and 0.7–1.2 mg/dL for creatinine.Liver injury was defined as an increase of over 5 × the upper limit of normal (ULN) ALT (ULNALT) and/or an increase of over 2 × the ULN ALP (ULNALP) according to the updated Roussel Uclaf causality assessment method [31]. We also categorized the reaction types using the R ratio: R ratio = (ALT/ULNALT)/(ALP/ULNALP). Liver injury was categorized as follows: hepatocellular: R > 5 and ALT >2 × ULNALT; cholestatic: R < 2 and ALP >2 × ULNALP; mixed: 2 < R < 5, and both ALT, ALP >2 × ULN. Drug-induced liver injury (DILI) may be hepatocellular or mixed.The criteria for suspected kidney disease for screening tests defined by the Ministry of Health and Welfare of Korea are as follows: level of creatinine is greater than 1.5 mg/dL and (b) estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease equation is lower than 60 mL/min/1.73 m2. The Modification of Diet in Renal Disease equation is as follows: 186 × (creatinine/88.4)−1.154 × (age)−0.203 × (0.742 if female) × (1.210 if black).


## 2.7. Statistical Analysis

The statistical analyses were performed using SAS® version 9.4 (SAS Institute, Inc.). The demographic characteristics of the participants presented are based on descriptive analyses. Continuous data are presented as mean ± SD, and they were analyzed using the independent two-samplet-test or the Wilcoxon signed-rank test for two groups and analysis for variance (ANOVA) for more than two groups. Binary data are presented as number (%), and they were analyzed using the chi-squared or Fisher’s exact test. All the tests were two-sided, and a P value of <0.05 was considered statistically significant. The effect size was reported by Cohen’s d.


## 3. Results

### 3.1. General Characteristics of the Participants and the Interventions

We enrolled a total of 1002 participants from several clinics. Of them, 500 fulfilled all the inclusion criteria (Figure1).Figure 1
Selection process for the retrospective chart review.Table2 provides the general characteristics of the participants. The mean age was 74.60 years (SD ± 6.07), and 83.40% of the sample were female. The participants were grouped by the type of management as follows: (a) the overall group received all types of interventions; (b) the herbal decoction group received a combination of herbal decoction and acupuncture; (c) the herbal extract group received a combination of herbal extract and acupuncture; (d) the acupuncture group received only. There were no differences in baseline ages, gender, and the MMSE-DS and MoCA-K scores between the groups. In contrast, the GDSSF-K scores of the groups were significantly different. The number of acupuncture sessions also differed across the groups, but the difference was not clinically meaningful. The durations of herbal medicine treatment of the herbal decoction and herbal extract groups were different; the duration of herbal medicine treatment was 16.14 (SD ± 2.46) days for herbal decoction and 42.20 (SD ± 18.53) days for herbal extract.Table 2
General characteristics of beneficiaries of the Korean Medicine Senior Health Promotion Program at Korean medicine clinics.
Overall (n = 500)GroupsHerbal decoction + acupuncture (n = 368)Herbal extract + acupuncture (n = 66)Only acupuncture (n = 66)PAge (years), M ± SD74.60 ± 6.0774.62 ± 6.0474.08 ± 6.0575.02 ± 6.350.6699Female,n (%)417 (83.40)311 (84.51)50 (75.76)56 (84.85)0.2006MMSE-DS, M ± SD23.25 ± 3.8623.44 ± 3.7322.73 ± 4.4122.71 ± 3.960.1822MoCA-K, M ± SD17.23 ± 4.1317.49 ± 3.8615.79 ± 4.9717.26 ± 4.420.0084GDSSF-K, M ± SD7.39 ± 4.207.71 ± 4.157.77 ± 4.205.23 ± 3.87<0.0001Acupuncture sessions, M ± SD17.74 ± 3.4117.27 ± 3.5518.92 ± 2.7819.18 ± 2.38<0.0001Herbal medicine duration, M ± SD20.05 ± 11.9616.14 ± 2.4642.21 ± 18.53None<0.0001Figure2 shows the proportion of herbal formulas prescribed during KSHPP. Among the five herbal formulas, Guibi-tang and modified Guibi-tang were the most frequently used (79.5%, 81.3%, and 69.7% for total herbal medicine, herbal decoction, and herbal extract, respectively). The second most common herbal medicine was Jowiseungcheong-tang in the herbal decoction group (9.8%) and Cheonwangbosim-dan in the herbal extract group (15.2%). Hwangnyeonhaedok-tang was prescribed the least, of the standardized five formulas.Figure 2
Proportion of herbal formulas prescribed during the Korean Medicine Senior Health Promotion Program at Korean medicine clinics.


### 3.2. Assessment of Overall Effectiveness

Table3 provides the changes in the scores of the outcomes. We assessed effectiveness against comorbid depression.Table 3
Changes in the cognitive screening test and geriatric depression scale scores.
Overall (n = 500)Herbal decoction + acupuncture (n = 368)Herbal extract + acupuncture (n = 66)Only acupuncture (n = 66)PrePostPPrePostPPrePostPPrePostPMoCA-K M ± SD (n)17.23 ± 4.13 (500)20.00 ± 5.14 (500)<0.000117.49 ± 3.86 (368)20.14 ± 4.99 (368)<0.000115.79 ± 4.97 (66)19.30 ± 5.57 (66)<0.000117.26 ± 4.42 (66)19.97 ± 5.52 (66)<0.0001Nondepressed (GDSSF-K < 5)16.81 ± 4.22 (136)18.39 ± 5.61 (136)<0.000116.83 ± 4.08 (84)17.49 ± 5.58 (84)0.314715.12 ± 5.09 (17)19.47 ± 6.26 (17)0.001717.57 ± 3.98 (35)20.03 ± 5.04 (35)<0.0001Depressed (GDSSF-K ≥ 5)17.39 ± 4.09 (364)20.61 ± 4.82 (364)<0.000117.68 ± 3.78 (284)20.92 ± 4.52 (284)<0.000116.26 ± 4.96 (49)19.24 ± 5.39 (49)<0.000116.90 ± 4.91 (31)19.90 ± 6.10 (31)<0.0001MMSE-DS M ± SD (n)23.25 ± 3.86 (500)25.44 ± 3.52 (500)<0.000123.44 ± 3.73 (368)25.44 ± 3.50 (368)<0.000122.73 ± 4.41 (66)25.30 ± 4.06 (66)<0.000122.71 ± 3.96 (66)25.61 ± 3.10 (66)<0.0001Nondepressed (GDSSF-K < 5)23.38 ± 4.28 (136)24.71 ± 3.78 (136)<0.000123.71 ± 4.42 (84)24.11 ± 4.09 (84)0.420924.00 ± 4.15 (17)25.88 ± 3.35 (17)0.032622.26 ± 3.90 (35)25.57 ± 2.85 (35)<0.0001Depressed (GDSSF-K ≥ 5)23.21 ± 3.70 (364)25.72 ± 3.39 (364)<0.000123.36 ± 3.51 (284)25.83 ± 3.21 (284)<0.000122.29 ± 4.45 (49)25.10 ± 4.29 (49)<0.000123.23 ± 4.04 (31)25.65 ± 3.41 (31)<0.0001GDSSF-K M ± SD (n)7.39 ± 4.20 (500)5.66 ± 4.14 (500)<0.00017.71 ± 4.15 (368)5.70 ± 4.09 (368)<0.00017.77 ± 4.20 (66)6.44 ± 4.64 (66)0.00245.23 ± 3.87 (66)4.62 ± 3.76 (66)0.0661Nondepressed (GDSSF-K < 5)2.14 ± 1.29 (136)2.14 ± 1.99 (136)0.43112.08 ± 1.32 (84)2.04 ± 1.88 (84)0.14742.12 ± 1.17 (17)1.94 ± 2.49 (17)0.61612.29 ± 1.30 (35)2.49 ± 1.99 (35)0.5800Depressed (GDSSF-K ≥ 5)9.35 ± 3.07 (364)6.97 ± 3.97 (364)<0.00019.37 ± 3.10 (284)6.79 ± 3.94 (284)<0.00019.73 ± 2.86 (49)8.00 ± 4.18 (49)0.00178.55 ± 8.55 (31)7.03 ± 3.84 (31)0.0071Overall, 364 patients (72.8%) were depressed and 136 (27.2%) were not. The mean MoCA-K score significantly increased by 2.77 points, whereas the mean MMSE-DS scores significantly increased by 2.19 points in the total sample (allP<0.0001). The scores of MoCA-K and MMSE-DS significantly increased in both depressed and nondepressed samples (all P<0.0001). The mean GDSSF-K score significantly decreased by 1.73 points in the total sample and 2.68 points in the depressed sample (all P<0.0001). However, the GDSSF-K score did not significantly change in the nondepressed sample (P=0.4311).In the herbal decoction group, 284 patients (77.2%) were depressed and 136 (22.8%) were not. The mean MoCA-K and MMSE-DS scores significantly increased by 2.65 and 2.00 points, respectively, in the total sample (allP<0.0001). The MoCA-K and MMSE-DS scores significantly increased in the depressed sample (all P<0.0001); they did not increase in the nondepressed sample (P=0.3147, P=0.4209, respectively). The mean GDSSF-K score significantly decreased by 2.01 points in the total sample and 2.61 points in the depressed sample (all P<0.0001). However, the GDSSF-K score did not significantly change in the nondepressed sample (P<0.0001).In the herbal extract group, 49 patients (74.2%) were depressed and 17 (25.8%) were not. The mean MoCA-K and MMSE-DS scores significantly increased by 3.51 and 2.57 points in the total sample (allP<0.0001). The MoCA-K score significantly increased in both depressed and nondepressed samples (all P<0.0001). The MMSE-DS score also significantly increased in the depressed (P<0.0001) and nondepressed (P=0.0326) samples. The mean GDSSF-K score significantly decreased by 1.33 points in the total sample and 1.73 points in the depressed sample (P=0.0024, P=0.0017, respectively). However, the GDSSF-K score did not significantly change in the nondepressed sample (P<0.6161).In the acupuncture group, 31 patients (46.7%) were depressed and 35 (53.0%) were not. The mean MoCA-K and MMSE-DS scores significantly increased by 2.71 and 2.90 points, respectively, in the total sample (allP<0.0001). The MoCA-K and MMSE-DS scores significantly increased in both depressed and nondepressed samples (all P<0.0001). The mean GDSSF-K score significantly decreased by 1.52 points in the depressed sample (P<0.0071). However, the change in the GDSSF-K score was not significant in the total and nondepressed samples (P=0.0661, P=0.5800, respectively).


### 3.3. Assessment of Effectiveness according to Adjunctive Herbal Medicine Formula

As most participants had been prescribed only one type of herbal medicine formula during the program, the effect size of each subgroup, which was divided according to the type of formula, was calculated. However, since the number of participants in each subgroup varied, comparisons between subgroups were not possible.Table4 provides the changes in the outcomes of the participants who received herbal medicine decoction and acupuncture treatment. As mentioned above, most of the participants who were certain of the type of herbal medicine formula took Guibi-tang and modified Guibi-tang (299/354; 84.5%). The number of participants who took other formulas varied from 9 to 36. The within-group effect sizes were reported by Cohen’s d.Table 4
Effectiveness of adjunctive herbal medicine decoction according to type of herbal medicine formula.
VariablesGuibi-tang (modified or not)Cheonwangbosim-danJowiseungcheong-tangHwangnyeonhaedok-tangPrePostP valueCohen’sdPrePostP valueCohen’sdPrePostP valueCohen’sdPrePostP valueCohen’sdOverallMoCA-K17.60 ± 3.76 (299)20.22 ± 4.88 (299)<0.00010.7918.40 ± 3.37 (10)21.20 ± 5.63 (10)0.07810.6616.72 ± 4.37 (36)18.53 ± 5.50 (36)0.00070.6117.11 ± 4.65 (9)22.56 ± 4.22 (9)0.00391.40MMSE-DS23.52 ± 3.71 (299)25.55 ± 3.51 (299)<0.00010.6624.50 ± 2.95 (10)26.30 ± 2.26 (10)0.01560.7722.69 ± 4.09 (36)24.50 ± 3.80 (36)<.00010.7823.22 ± 3.42 (9)26.44 ± 2.55 (9)0.01561.24GDSSF-K7.40 ± 4.15 (299)5.52 ± 4.00 (299)<0.0001−0.648.00 ± 3.02 (10)4.90 ± 3.03 (10)0.0117−0.938.67 ± 4.24 (36)7.03 ± 4.49 (36)0.0004−0.629.89 ± 3.55 (9)4.44 ± 4.22 (9)0.0039−1.57Nondepressed (GDSSF-K < 5)MoCA-K16.82 ± 4.20 (77)17.70 ± 5.71 (77)0.10780.2519.00 (1)18.00 (1)>0.999916.67 ± 2.73 (6)14.67 ± 3.14 (6)0.0313−2.25MMSE-DS23.84 ± 4.29 (77)24.18 ± 4.14 (77)0.48680.1128.00 (1)29.00 (1)>0.999921.33 ± 5.82 (6)22.33 ± 2.88 (6)0.87500.26GDSSF-K2.09 ± 1.36 (77)2.05 ± 1.95 (77)0.1828−0.022.00 (1)3.00 (1)>0.99992.00 ± 0.89 (6)1.67 ± 0.52 (6)0.6875−0.32Depressed (GDSSF-K ≥ 5)MoCA-K17.87 ± 3.56 (222)21.09 ± 4.24 (222)<0.00011.0718.33 ± 3.57 (9)21.56 ± 5.85 (9)0.03130.7516.73 ± 4.66 (30)19.30 ± 5.58 (30)<.00010.9817.11 ± 4.65 (9)22.56 ± 4.22 (9)0.00391.40MMSE-DS23.41 ± 3.49 (222)26.02 ± 3.13 (222)<0.00010.9324.11 ± 2.85 (9)26.00 ± 2.18 (9)0.03130.7722.97 ± 3.73 (30)24.93 ± 3.85 (30)<.00011.0323.22 ± 3.42 (9)26.44 ± 2.55 (9)0.01561.24GDSSF-K9.24 ± 3.05 (222)6.72 ± 3.83 (222)<0.0001−0.848.67 ± 2.29 (9)5.11 ± 3.14 (9)0.0078−1.1110.00 ± 3.24 (30)8.10 ± 4.15 (30)0.0006−0.689.89 ± 3.55 (9)4.44 ± 4.22 (9)0.0039−1.57In the Guibi-tang and modified Guibi-tang groups, the overall effect sizes were medium across all outcomes (Cohen’sd was 0.79, 0.66, and −0.64 for MoCA-K, MMSE-DS, and GDSSF-K, respectively). The effect sizes were large across all outcomes in depressed samples (Cohen’s d was 1.07, 0.93, and −0.84 for MoCA-K, MMSE-DS, and GDSSF-K, respectively), whereas the effect sizes were very small or small for cognitive function in nondepressed samples (Cohen’s d was 0.25 and 0.11 for MoCA-K and MMSE-DS, respectively).In the Cheonwangbosim-dan group, the overall effect sizes were medium for cognitive function (Cohen’sd = 0.66 for MoCA-K and 0.77 for MMSE-DS). The overall effect size was large for GDSSF-K (Cohen’s d = −0.93). All participants, except one, were depressed.In the Jowiseungcheong-tang group, the overall effect sizes were medium across all outcomes (Cohen’sd was 0.61, 0.78, and −0.62 for MoCA-K, MMSE-DS, and GDSSF-K, respectively). The effect sizes were large for cognitive function (Cohen’s d was 0.98 and 1.03 for MoCA-K and MMSE-DS, respectively), and medium for GDSSF-K (Cohen’s d = −0.68) in depressed samples. In contrast, the effect was negative for MoCA-K (Cohen’s d = −2.25), and the effect sizes were small for MMSE-DS (Cohen’s d = 0.26) in nondepressed samples.In the Hwangnyeonhaedok-tang group, all participants were depressed. The effect sizes were large across all outcomes (Cohen’sd was 1.40, 1.24, and −1.57 for MoCA-K, MMSE-DS, and GDSSF-K, respectively).Table5 provides the changes in the outcomes of the participants who received herbal medicine extract and acupuncture treatment. Most of the participants who were certain of the type of herbal medicine formula took Guibi-tang and modified Guibi-tang (46/62; 74.2%). The number of participants who took Cheonwangbosim-dan and Hwangnyeonhaedok-tang was 10 and 6, respectively. The within-group effect sizes were also reported by Cohen’s d.Table 5
Effectiveness of adjunctive herbal medicine extracts according to type of herbal medicine formula.
VariablesGuibi-tang (modified or not)Cheonwangbosim-danHwangnyeonhaedok-tangPrePostP valueCohen’sdPrePostP valueCohen’sdPrePostP valueCohen’sdOverallMoCA-K16.78 ± 4.41 (46)20.13 ± 5.17 (46)<0.00010.9613.10 ± 6.51 (10)17.30 ± 7.83 (10)0.00390.9513.83 ± 3.06 (6)18.00 ± 2.28 (6)0.03131.87MMSE-DS23.39 ± 3.96 (46)25.52 ± 3.69 (46)<0.00010.7621.80 ± 4.89 (10)24.80 ± 3.68 (10)0.01561.2021.33 ± 4.68 (6)26.67 ± 2.34 (6)0.03131.85GDSSF-K8.39 ± 4.11 (46)6.93 ± 4.66 (46)0.0050–0.426.20 ± 4.42 (10)4.70 ± 4.24 (10)0.2969–0.495.33 ± 3.20 (6)5.83 ± 4.36 (6)0.34380.22Nondepressed (GDSSF-K < 5)MoCA-K17.60 ± 3.75 (10)20.90 ± 6.14 (10)0.04690.7612.25 ± 5.91 (4)18.50 ± 7.85 (4)0.25000.9312.00 ± 4.24 (2)18.50 ± 2.12 (2)0.50003.07MMSE-DS25.30 ± 3.43 (10)26.00 ± 3.50 (10)0.57810.2522.00 ± 4.24 (4)25.25 ± 3.77 (4)0.25001.3023.00 ± 8.49 (2)28.00 ± 2.83 (2)0.50000.88GDSSF-K2.30 ± 1.06 (10)2.20 ± 3.12 (10)0.7031–0.042.00 ± 0.82 (4)2.25 ± 1.26 (4)>0.99990.262.00 ± 2.83 (2)0.50 ± 0.71 (2)>0.9999–0.42Depressed (GDSSF-K ≥ 5)MoCA-K16.56 ± 4.59 (36)19.92 ± 4.94 (36)<0.00011.0213.67 ± 7.37 (6)16.50 ± 8.46 (6)0.03131.9314.75 ± 2.50 (4)17.75 ± 2.63 (4)0.12502.61MMSE-DS22.86 ± 3.97 (36)25.39 ± 3.77 (36)<0.00010.9421.67 ± 5.68 (6)24.50 ± 3.94 (6)0.12501.0420.50 ± 3.11 (4)26.00 ± 2.16 (4)0.12503.18GDSSF-K10.08 ± 2.80 (36)8.25 ± 4.15 (36)0.0028–0.519.00 ± 3.35 (6)6.33 ± 4.84 (6)0.1875–0.767.00 ± 1.83 (4)8.50 ± 1.73 (4)0.12502.59In the Guibi-tang and modified Guibi-tang group, the overall effect size was large for MoCA-K (Cohen’sd = 0.96) and medium for MMSE-DS (Cohen’s d = 0.76). The overall effect size for GDSSF-K was small (Cohen’s d = −0.42). The effect sizes for cognitive function were larger in depressed samples than nondepressed samples (Cohen’s d = 0.76 versus 1.02 for MoCA-K, and 0.25 versus 0.97 for MMSE-DS). The effect size (Cohen’s d) was −0.51 for GDSSF-K in depressed samples.In the Cheonwangbosim-dan group, the effect sizes (Cohen’sd) for cognitive function were large in the overall, nondepressed, and depressed samples. The effect size for GDSSF-K was small and medium in all samples and depressed samples, respectively (Cohen’s d was −0.79 versus −0.76).In the Hwangnyeonhaedok-tang group, the effect sizes (Cohen’sd) for cognitive function were large in the overall, nondepressed, and depressed samples. The effect on GDSSF-K was not significant.


### 3.4. Safety

Table6 provides that the changes in the mean outcomes of LFT and RFT were mostly not significant (P>0.05). The levels of ALT in the overall and herbal extract groups, the levels of DB in the herbal decoction group, the level of ALP in all groups, and the level of creatinine in the herbal extract group slightly increased, but the change was not clinically meaningful when considering the reference range.Table 6
Changes in biochemical examination findings.
Overall (n = 434)Herbal decoction + acupuncture (n = 368)Herbal extract + acupuncture (n = 66)PrePostPPrePostPPrePostPAST, M ± SD (n)26.90 ± 8.51 (408)27.38 ± 9.27 (353)0.144127.25 ± 8.87 (344)27.66 ± 9.74 (293)0.202725.03 ± 5.95 (64)26.00 ± 6.37(60)0.4183ALT, M ± SD (n)20.60 ± 9.60 (408)21.90 ± 11.28 (353)0.034320.97 ± 9.56 (344)22.19 ± 11.67 (293)0.156018.56 ± 9.66 (64)20.45 ± 9.03 (60)0.0289TB, M ± SD (n)0.69 ± 0.26 (403)0.71 ± 0.26 (352)0.09270.70 ± 0.27 (339)0.71 ± 0.26 (292)0.31060.66 ± 0.22 (64)0.70 ± 0.26 (60)0.0644DB, M ± SD (n)0.13 ± 0.05 (400)0.13 ± 0.05 (351)0.32010.13 ± 0.05 (337)0.13 ± 0.05 (291)0.03930.14 ± 0.08 (63)0.15 ± 0.08 (63)0.1421ALP, M ± SD (n)84.20 ± 49.13 (404)87.86 ± 53.84 (353)0.001677.61 ± 40.70 (340)79.97 ± 43.49 (293)0.0359119.17 ± 71.07 (64)126.42 ± 78.17 (60)0.0030GGT, M ± SD (n)22.67 ± 17.18 (407)22.84 ± 17.41 (352)0.977622.32 ± 16.41 (343)22.07 ± 14.62 (292)0.894724.56 ± 20.88 (64)26.57 ± 27.04 (60)0.6835BUN, M ± SD (n)16.52 ± 4.26 (405)16.57 ± 4.28 (353)0.319716.55 ± 4.24 (341)16.40 ± 4.25 (293)0.766716.34 ± 4.36 (64)17.39 ± 4.36 (60)0.0633Creatinine, M ± SD (n)0.87 ± 0.18 (407)0.87 ± 0.17 (353)0.40260.87 ± 0.17 (343)0.86 ± 0.16 (293)0.91470.88 ± 0.22 (64)0.92 ± 0.20 (60)0.0446Of the 434 participants who were treated with herbal medicine, the data of 341 were used for the assessment of hepatotoxicity and nephrotoxicity. All the participants were monitored during herbal medicine treatment by doctors of Korean medicine, and their conventional medications (e.g., blood pressure medications, lipid-lowering drugs, and tranquilizers) were maintained.In terms of liver function, 11 participants (3.23%) showed evidence of liver injury with over 2 × ULNALP, whereas 330 did not at baseline. Of the 11 cases of liver injury present at baseline, 9 still met the criteria of liver injury at the endpoint. Of the 330 patients without liver injury at baseline, 3 (0.91%) developed liver injuries with over 2 × ULNALP during KSHPP. However, all the reactions of the 3 participants were cholestatic with the R ratio ranging from 0.17 to 0.23; the level of ALP also increased by 192–237 at the baseline. In summary, of the 14 cases, 11 were considered prevalent and 3 had slightly increased ALP levels, but their liver injury type was cholestatic, and all the cases were excluded from DILI.In terms of renal function, two participants (0.59%) showed evidence of suspected kidney disease, whereas 339 did not at baseline. Of the two cases of suspected kidney disease, one still met the criterion of renal dysfunction at the endpoint. Of the 339 patients without evidence of suspected kidney disease at baseline, one (0.29%) met the criteria at the endpoint. For that case, the creatinine level was 1.5 mg/dL and eGFR was 47.62 mL/min/1.73 m2 at baseline, and they changed to 1.53 mg/dL and 46.55 mL/min/1.73 m2, respectively, at the endpoint. eGFR within the range of 45–59 mL/min/1.73 m2 was graded as the G3a stage of chronic kidney disease according to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline [32]. In summary, of the 3 cases, 2 were considered prevalent, and 1 had a slightly increased creatinine level without a change in the stage of chronic kidney disease. Thus, no evident cases implied drug-induced kidney disease.A detailed profile of the participants with newly suspected kidney disease or liver injury at the endpoint is presented in Supplementary Table1. This table provides their clinical characteristics (i.e., medical, family, and social history), prescription details, and results of laboratory testing.


## 3.1. General Characteristics of the Participants and the Interventions

We enrolled a total of 1002 participants from several clinics. Of them, 500 fulfilled all the inclusion criteria (Figure1).Figure 1
Selection process for the retrospective chart review.Table2 provides the general characteristics of the participants. The mean age was 74.60 years (SD ± 6.07), and 83.40% of the sample were female. The participants were grouped by the type of management as follows: (a) the overall group received all types of interventions; (b) the herbal decoction group received a combination of herbal decoction and acupuncture; (c) the herbal extract group received a combination of herbal extract and acupuncture; (d) the acupuncture group received only. There were no differences in baseline ages, gender, and the MMSE-DS and MoCA-K scores between the groups. In contrast, the GDSSF-K scores of the groups were significantly different. The number of acupuncture sessions also differed across the groups, but the difference was not clinically meaningful. The durations of herbal medicine treatment of the herbal decoction and herbal extract groups were different; the duration of herbal medicine treatment was 16.14 (SD ± 2.46) days for herbal decoction and 42.20 (SD ± 18.53) days for herbal extract.Table 2
General characteristics of beneficiaries of the Korean Medicine Senior Health Promotion Program at Korean medicine clinics.
Overall (n = 500)GroupsHerbal decoction + acupuncture (n = 368)Herbal extract + acupuncture (n = 66)Only acupuncture (n = 66)PAge (years), M ± SD74.60 ± 6.0774.62 ± 6.0474.08 ± 6.0575.02 ± 6.350.6699Female,n (%)417 (83.40)311 (84.51)50 (75.76)56 (84.85)0.2006MMSE-DS, M ± SD23.25 ± 3.8623.44 ± 3.7322.73 ± 4.4122.71 ± 3.960.1822MoCA-K, M ± SD17.23 ± 4.1317.49 ± 3.8615.79 ± 4.9717.26 ± 4.420.0084GDSSF-K, M ± SD7.39 ± 4.207.71 ± 4.157.77 ± 4.205.23 ± 3.87<0.0001Acupuncture sessions, M ± SD17.74 ± 3.4117.27 ± 3.5518.92 ± 2.7819.18 ± 2.38<0.0001Herbal medicine duration, M ± SD20.05 ± 11.9616.14 ± 2.4642.21 ± 18.53None<0.0001Figure2 shows the proportion of herbal formulas prescribed during KSHPP. Among the five herbal formulas, Guibi-tang and modified Guibi-tang were the most frequently used (79.5%, 81.3%, and 69.7% for total herbal medicine, herbal decoction, and herbal extract, respectively). The second most common herbal medicine was Jowiseungcheong-tang in the herbal decoction group (9.8%) and Cheonwangbosim-dan in the herbal extract group (15.2%). Hwangnyeonhaedok-tang was prescribed the least, of the standardized five formulas.Figure 2
Proportion of herbal formulas prescribed during the Korean Medicine Senior Health Promotion Program at Korean medicine clinics.


## 3.2. Assessment of Overall Effectiveness

Table3 provides the changes in the scores of the outcomes. We assessed effectiveness against comorbid depression.Table 3
Changes in the cognitive screening test and geriatric depression scale scores.
Overall (n = 500)Herbal decoction + acupuncture (n = 368)Herbal extract + acupuncture (n = 66)Only acupuncture (n = 66)PrePostPPrePostPPrePostPPrePostPMoCA-K M ± SD (n)17.23 ± 4.13 (500)20.00 ± 5.14 (500)<0.000117.49 ± 3.86 (368)20.14 ± 4.99 (368)<0.000115.79 ± 4.97 (66)19.30 ± 5.57 (66)<0.000117.26 ± 4.42 (66)19.97 ± 5.52 (66)<0.0001Nondepressed (GDSSF-K < 5)16.81 ± 4.22 (136)18.39 ± 5.61 (136)<0.000116.83 ± 4.08 (84)17.49 ± 5.58 (84)0.314715.12 ± 5.09 (17)19.47 ± 6.26 (17)0.001717.57 ± 3.98 (35)20.03 ± 5.04 (35)<0.0001Depressed (GDSSF-K ≥ 5)17.39 ± 4.09 (364)20.61 ± 4.82 (364)<0.000117.68 ± 3.78 (284)20.92 ± 4.52 (284)<0.000116.26 ± 4.96 (49)19.24 ± 5.39 (49)<0.000116.90 ± 4.91 (31)19.90 ± 6.10 (31)<0.0001MMSE-DS M ± SD (n)23.25 ± 3.86 (500)25.44 ± 3.52 (500)<0.000123.44 ± 3.73 (368)25.44 ± 3.50 (368)<0.000122.73 ± 4.41 (66)25.30 ± 4.06 (66)<0.000122.71 ± 3.96 (66)25.61 ± 3.10 (66)<0.0001Nondepressed (GDSSF-K < 5)23.38 ± 4.28 (136)24.71 ± 3.78 (136)<0.000123.71 ± 4.42 (84)24.11 ± 4.09 (84)0.420924.00 ± 4.15 (17)25.88 ± 3.35 (17)0.032622.26 ± 3.90 (35)25.57 ± 2.85 (35)<0.0001Depressed (GDSSF-K ≥ 5)23.21 ± 3.70 (364)25.72 ± 3.39 (364)<0.000123.36 ± 3.51 (284)25.83 ± 3.21 (284)<0.000122.29 ± 4.45 (49)25.10 ± 4.29 (49)<0.000123.23 ± 4.04 (31)25.65 ± 3.41 (31)<0.0001GDSSF-K M ± SD (n)7.39 ± 4.20 (500)5.66 ± 4.14 (500)<0.00017.71 ± 4.15 (368)5.70 ± 4.09 (368)<0.00017.77 ± 4.20 (66)6.44 ± 4.64 (66)0.00245.23 ± 3.87 (66)4.62 ± 3.76 (66)0.0661Nondepressed (GDSSF-K < 5)2.14 ± 1.29 (136)2.14 ± 1.99 (136)0.43112.08 ± 1.32 (84)2.04 ± 1.88 (84)0.14742.12 ± 1.17 (17)1.94 ± 2.49 (17)0.61612.29 ± 1.30 (35)2.49 ± 1.99 (35)0.5800Depressed (GDSSF-K ≥ 5)9.35 ± 3.07 (364)6.97 ± 3.97 (364)<0.00019.37 ± 3.10 (284)6.79 ± 3.94 (284)<0.00019.73 ± 2.86 (49)8.00 ± 4.18 (49)0.00178.55 ± 8.55 (31)7.03 ± 3.84 (31)0.0071Overall, 364 patients (72.8%) were depressed and 136 (27.2%) were not. The mean MoCA-K score significantly increased by 2.77 points, whereas the mean MMSE-DS scores significantly increased by 2.19 points in the total sample (allP<0.0001). The scores of MoCA-K and MMSE-DS significantly increased in both depressed and nondepressed samples (all P<0.0001). The mean GDSSF-K score significantly decreased by 1.73 points in the total sample and 2.68 points in the depressed sample (all P<0.0001). However, the GDSSF-K score did not significantly change in the nondepressed sample (P=0.4311).In the herbal decoction group, 284 patients (77.2%) were depressed and 136 (22.8%) were not. The mean MoCA-K and MMSE-DS scores significantly increased by 2.65 and 2.00 points, respectively, in the total sample (allP<0.0001). The MoCA-K and MMSE-DS scores significantly increased in the depressed sample (all P<0.0001); they did not increase in the nondepressed sample (P=0.3147, P=0.4209, respectively). The mean GDSSF-K score significantly decreased by 2.01 points in the total sample and 2.61 points in the depressed sample (all P<0.0001). However, the GDSSF-K score did not significantly change in the nondepressed sample (P<0.0001).In the herbal extract group, 49 patients (74.2%) were depressed and 17 (25.8%) were not. The mean MoCA-K and MMSE-DS scores significantly increased by 3.51 and 2.57 points in the total sample (allP<0.0001). The MoCA-K score significantly increased in both depressed and nondepressed samples (all P<0.0001). The MMSE-DS score also significantly increased in the depressed (P<0.0001) and nondepressed (P=0.0326) samples. The mean GDSSF-K score significantly decreased by 1.33 points in the total sample and 1.73 points in the depressed sample (P=0.0024, P=0.0017, respectively). However, the GDSSF-K score did not significantly change in the nondepressed sample (P<0.6161).In the acupuncture group, 31 patients (46.7%) were depressed and 35 (53.0%) were not. The mean MoCA-K and MMSE-DS scores significantly increased by 2.71 and 2.90 points, respectively, in the total sample (allP<0.0001). The MoCA-K and MMSE-DS scores significantly increased in both depressed and nondepressed samples (all P<0.0001). The mean GDSSF-K score significantly decreased by 1.52 points in the depressed sample (P<0.0071). However, the change in the GDSSF-K score was not significant in the total and nondepressed samples (P=0.0661, P=0.5800, respectively).


## 3.3. Assessment of Effectiveness according to Adjunctive Herbal Medicine Formula

As most participants had been prescribed only one type of herbal medicine formula during the program, the effect size of each subgroup, which was divided according to the type of formula, was calculated. However, since the number of participants in each subgroup varied, comparisons between subgroups were not possible.Table4 provides the changes in the outcomes of the participants who received herbal medicine decoction and acupuncture treatment. As mentioned above, most of the participants who were certain of the type of herbal medicine formula took Guibi-tang and modified Guibi-tang (299/354; 84.5%). The number of participants who took other formulas varied from 9 to 36. The within-group effect sizes were reported by Cohen’s d.Table 4
Effectiveness of adjunctive herbal medicine decoction according to type of herbal medicine formula.
VariablesGuibi-tang (modified or not)Cheonwangbosim-danJowiseungcheong-tangHwangnyeonhaedok-tangPrePostP valueCohen’sdPrePostP valueCohen’sdPrePostP valueCohen’sdPrePostP valueCohen’sdOverallMoCA-K17.60 ± 3.76 (299)20.22 ± 4.88 (299)<0.00010.7918.40 ± 3.37 (10)21.20 ± 5.63 (10)0.07810.6616.72 ± 4.37 (36)18.53 ± 5.50 (36)0.00070.6117.11 ± 4.65 (9)22.56 ± 4.22 (9)0.00391.40MMSE-DS23.52 ± 3.71 (299)25.55 ± 3.51 (299)<0.00010.6624.50 ± 2.95 (10)26.30 ± 2.26 (10)0.01560.7722.69 ± 4.09 (36)24.50 ± 3.80 (36)<.00010.7823.22 ± 3.42 (9)26.44 ± 2.55 (9)0.01561.24GDSSF-K7.40 ± 4.15 (299)5.52 ± 4.00 (299)<0.0001−0.648.00 ± 3.02 (10)4.90 ± 3.03 (10)0.0117−0.938.67 ± 4.24 (36)7.03 ± 4.49 (36)0.0004−0.629.89 ± 3.55 (9)4.44 ± 4.22 (9)0.0039−1.57Nondepressed (GDSSF-K < 5)MoCA-K16.82 ± 4.20 (77)17.70 ± 5.71 (77)0.10780.2519.00 (1)18.00 (1)>0.999916.67 ± 2.73 (6)14.67 ± 3.14 (6)0.0313−2.25MMSE-DS23.84 ± 4.29 (77)24.18 ± 4.14 (77)0.48680.1128.00 (1)29.00 (1)>0.999921.33 ± 5.82 (6)22.33 ± 2.88 (6)0.87500.26GDSSF-K2.09 ± 1.36 (77)2.05 ± 1.95 (77)0.1828−0.022.00 (1)3.00 (1)>0.99992.00 ± 0.89 (6)1.67 ± 0.52 (6)0.6875−0.32Depressed (GDSSF-K ≥ 5)MoCA-K17.87 ± 3.56 (222)21.09 ± 4.24 (222)<0.00011.0718.33 ± 3.57 (9)21.56 ± 5.85 (9)0.03130.7516.73 ± 4.66 (30)19.30 ± 5.58 (30)<.00010.9817.11 ± 4.65 (9)22.56 ± 4.22 (9)0.00391.40MMSE-DS23.41 ± 3.49 (222)26.02 ± 3.13 (222)<0.00010.9324.11 ± 2.85 (9)26.00 ± 2.18 (9)0.03130.7722.97 ± 3.73 (30)24.93 ± 3.85 (30)<.00011.0323.22 ± 3.42 (9)26.44 ± 2.55 (9)0.01561.24GDSSF-K9.24 ± 3.05 (222)6.72 ± 3.83 (222)<0.0001−0.848.67 ± 2.29 (9)5.11 ± 3.14 (9)0.0078−1.1110.00 ± 3.24 (30)8.10 ± 4.15 (30)0.0006−0.689.89 ± 3.55 (9)4.44 ± 4.22 (9)0.0039−1.57In the Guibi-tang and modified Guibi-tang groups, the overall effect sizes were medium across all outcomes (Cohen’sd was 0.79, 0.66, and −0.64 for MoCA-K, MMSE-DS, and GDSSF-K, respectively). The effect sizes were large across all outcomes in depressed samples (Cohen’s d was 1.07, 0.93, and −0.84 for MoCA-K, MMSE-DS, and GDSSF-K, respectively), whereas the effect sizes were very small or small for cognitive function in nondepressed samples (Cohen’s d was 0.25 and 0.11 for MoCA-K and MMSE-DS, respectively).In the Cheonwangbosim-dan group, the overall effect sizes were medium for cognitive function (Cohen’sd = 0.66 for MoCA-K and 0.77 for MMSE-DS). The overall effect size was large for GDSSF-K (Cohen’s d = −0.93). All participants, except one, were depressed.In the Jowiseungcheong-tang group, the overall effect sizes were medium across all outcomes (Cohen’sd was 0.61, 0.78, and −0.62 for MoCA-K, MMSE-DS, and GDSSF-K, respectively). The effect sizes were large for cognitive function (Cohen’s d was 0.98 and 1.03 for MoCA-K and MMSE-DS, respectively), and medium for GDSSF-K (Cohen’s d = −0.68) in depressed samples. In contrast, the effect was negative for MoCA-K (Cohen’s d = −2.25), and the effect sizes were small for MMSE-DS (Cohen’s d = 0.26) in nondepressed samples.In the Hwangnyeonhaedok-tang group, all participants were depressed. The effect sizes were large across all outcomes (Cohen’sd was 1.40, 1.24, and −1.57 for MoCA-K, MMSE-DS, and GDSSF-K, respectively).Table5 provides the changes in the outcomes of the participants who received herbal medicine extract and acupuncture treatment. Most of the participants who were certain of the type of herbal medicine formula took Guibi-tang and modified Guibi-tang (46/62; 74.2%). The number of participants who took Cheonwangbosim-dan and Hwangnyeonhaedok-tang was 10 and 6, respectively. The within-group effect sizes were also reported by Cohen’s d.Table 5
Effectiveness of adjunctive herbal medicine extracts according to type of herbal medicine formula.
VariablesGuibi-tang (modified or not)Cheonwangbosim-danHwangnyeonhaedok-tangPrePostP valueCohen’sdPrePostP valueCohen’sdPrePostP valueCohen’sdOverallMoCA-K16.78 ± 4.41 (46)20.13 ± 5.17 (46)<0.00010.9613.10 ± 6.51 (10)17.30 ± 7.83 (10)0.00390.9513.83 ± 3.06 (6)18.00 ± 2.28 (6)0.03131.87MMSE-DS23.39 ± 3.96 (46)25.52 ± 3.69 (46)<0.00010.7621.80 ± 4.89 (10)24.80 ± 3.68 (10)0.01561.2021.33 ± 4.68 (6)26.67 ± 2.34 (6)0.03131.85GDSSF-K8.39 ± 4.11 (46)6.93 ± 4.66 (46)0.0050–0.426.20 ± 4.42 (10)4.70 ± 4.24 (10)0.2969–0.495.33 ± 3.20 (6)5.83 ± 4.36 (6)0.34380.22Nondepressed (GDSSF-K < 5)MoCA-K17.60 ± 3.75 (10)20.90 ± 6.14 (10)0.04690.7612.25 ± 5.91 (4)18.50 ± 7.85 (4)0.25000.9312.00 ± 4.24 (2)18.50 ± 2.12 (2)0.50003.07MMSE-DS25.30 ± 3.43 (10)26.00 ± 3.50 (10)0.57810.2522.00 ± 4.24 (4)25.25 ± 3.77 (4)0.25001.3023.00 ± 8.49 (2)28.00 ± 2.83 (2)0.50000.88GDSSF-K2.30 ± 1.06 (10)2.20 ± 3.12 (10)0.7031–0.042.00 ± 0.82 (4)2.25 ± 1.26 (4)>0.99990.262.00 ± 2.83 (2)0.50 ± 0.71 (2)>0.9999–0.42Depressed (GDSSF-K ≥ 5)MoCA-K16.56 ± 4.59 (36)19.92 ± 4.94 (36)<0.00011.0213.67 ± 7.37 (6)16.50 ± 8.46 (6)0.03131.9314.75 ± 2.50 (4)17.75 ± 2.63 (4)0.12502.61MMSE-DS22.86 ± 3.97 (36)25.39 ± 3.77 (36)<0.00010.9421.67 ± 5.68 (6)24.50 ± 3.94 (6)0.12501.0420.50 ± 3.11 (4)26.00 ± 2.16 (4)0.12503.18GDSSF-K10.08 ± 2.80 (36)8.25 ± 4.15 (36)0.0028–0.519.00 ± 3.35 (6)6.33 ± 4.84 (6)0.1875–0.767.00 ± 1.83 (4)8.50 ± 1.73 (4)0.12502.59In the Guibi-tang and modified Guibi-tang group, the overall effect size was large for MoCA-K (Cohen’sd = 0.96) and medium for MMSE-DS (Cohen’s d = 0.76). The overall effect size for GDSSF-K was small (Cohen’s d = −0.42). The effect sizes for cognitive function were larger in depressed samples than nondepressed samples (Cohen’s d = 0.76 versus 1.02 for MoCA-K, and 0.25 versus 0.97 for MMSE-DS). The effect size (Cohen’s d) was −0.51 for GDSSF-K in depressed samples.In the Cheonwangbosim-dan group, the effect sizes (Cohen’sd) for cognitive function were large in the overall, nondepressed, and depressed samples. The effect size for GDSSF-K was small and medium in all samples and depressed samples, respectively (Cohen’s d was −0.79 versus −0.76).In the Hwangnyeonhaedok-tang group, the effect sizes (Cohen’sd) for cognitive function were large in the overall, nondepressed, and depressed samples. The effect on GDSSF-K was not significant.


## 3.4. Safety

Table6 provides that the changes in the mean outcomes of LFT and RFT were mostly not significant (P>0.05). The levels of ALT in the overall and herbal extract groups, the levels of DB in the herbal decoction group, the level of ALP in all groups, and the level of creatinine in the herbal extract group slightly increased, but the change was not clinically meaningful when considering the reference range.Table 6
Changes in biochemical examination findings.
Overall (n = 434)Herbal decoction + acupuncture (n = 368)Herbal extract + acupuncture (n = 66)PrePostPPrePostPPrePostPAST, M ± SD (n)26.90 ± 8.51 (408)27.38 ± 9.27 (353)0.144127.25 ± 8.87 (344)27.66 ± 9.74 (293)0.202725.03 ± 5.95 (64)26.00 ± 6.37(60)0.4183ALT, M ± SD (n)20.60 ± 9.60 (408)21.90 ± 11.28 (353)0.034320.97 ± 9.56 (344)22.19 ± 11.67 (293)0.156018.56 ± 9.66 (64)20.45 ± 9.03 (60)0.0289TB, M ± SD (n)0.69 ± 0.26 (403)0.71 ± 0.26 (352)0.09270.70 ± 0.27 (339)0.71 ± 0.26 (292)0.31060.66 ± 0.22 (64)0.70 ± 0.26 (60)0.0644DB, M ± SD (n)0.13 ± 0.05 (400)0.13 ± 0.05 (351)0.32010.13 ± 0.05 (337)0.13 ± 0.05 (291)0.03930.14 ± 0.08 (63)0.15 ± 0.08 (63)0.1421ALP, M ± SD (n)84.20 ± 49.13 (404)87.86 ± 53.84 (353)0.001677.61 ± 40.70 (340)79.97 ± 43.49 (293)0.0359119.17 ± 71.07 (64)126.42 ± 78.17 (60)0.0030GGT, M ± SD (n)22.67 ± 17.18 (407)22.84 ± 17.41 (352)0.977622.32 ± 16.41 (343)22.07 ± 14.62 (292)0.894724.56 ± 20.88 (64)26.57 ± 27.04 (60)0.6835BUN, M ± SD (n)16.52 ± 4.26 (405)16.57 ± 4.28 (353)0.319716.55 ± 4.24 (341)16.40 ± 4.25 (293)0.766716.34 ± 4.36 (64)17.39 ± 4.36 (60)0.0633Creatinine, M ± SD (n)0.87 ± 0.18 (407)0.87 ± 0.17 (353)0.40260.87 ± 0.17 (343)0.86 ± 0.16 (293)0.91470.88 ± 0.22 (64)0.92 ± 0.20 (60)0.0446Of the 434 participants who were treated with herbal medicine, the data of 341 were used for the assessment of hepatotoxicity and nephrotoxicity. All the participants were monitored during herbal medicine treatment by doctors of Korean medicine, and their conventional medications (e.g., blood pressure medications, lipid-lowering drugs, and tranquilizers) were maintained.In terms of liver function, 11 participants (3.23%) showed evidence of liver injury with over 2 × ULNALP, whereas 330 did not at baseline. Of the 11 cases of liver injury present at baseline, 9 still met the criteria of liver injury at the endpoint. Of the 330 patients without liver injury at baseline, 3 (0.91%) developed liver injuries with over 2 × ULNALP during KSHPP. However, all the reactions of the 3 participants were cholestatic with the R ratio ranging from 0.17 to 0.23; the level of ALP also increased by 192–237 at the baseline. In summary, of the 14 cases, 11 were considered prevalent and 3 had slightly increased ALP levels, but their liver injury type was cholestatic, and all the cases were excluded from DILI.In terms of renal function, two participants (0.59%) showed evidence of suspected kidney disease, whereas 339 did not at baseline. Of the two cases of suspected kidney disease, one still met the criterion of renal dysfunction at the endpoint. Of the 339 patients without evidence of suspected kidney disease at baseline, one (0.29%) met the criteria at the endpoint. For that case, the creatinine level was 1.5 mg/dL and eGFR was 47.62 mL/min/1.73 m2 at baseline, and they changed to 1.53 mg/dL and 46.55 mL/min/1.73 m2, respectively, at the endpoint. eGFR within the range of 45–59 mL/min/1.73 m2 was graded as the G3a stage of chronic kidney disease according to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline [32]. In summary, of the 3 cases, 2 were considered prevalent, and 1 had a slightly increased creatinine level without a change in the stage of chronic kidney disease. Thus, no evident cases implied drug-induced kidney disease.A detailed profile of the participants with newly suspected kidney disease or liver injury at the endpoint is presented in Supplementary Table1. This table provides their clinical characteristics (i.e., medical, family, and social history), prescription details, and results of laboratory testing.


## 4. Discussion

In this study, we conducted a retrospective study using the medical records of 500 MCI patients out of 1002 who received herbal medicine and acupuncture at KMC. We collected data from several clinics that had provided KSHPP to the participants.We analyzed the scores of MoCA-K, MMSE-DS, and GDSSF-K to assess the effectiveness of KSHPP. We found that the mean MoCA-K and MMSE-DS scores significantly increased by 2.77 and 2.19, respectively, whereas the mean GDSSF-K score significantly decreased by 1.73 in the entire sample (n = 500, all P<0.0001). All the intervention groups showed significant improvement in MoCA-K and MMSE-DS scores in all the cases, except for the nondepressed sample in the herbal decoction group. In addition, all the intervention groups showed a significant improvement in GDSSF-K scores in the depressed samples.When we divided subgroups according to types of adjunctive herbal medicine formula, the effect sizes (Cohen’sd) for cognitive function were medium or large in overall and depressed samples. The effect size of Hwangnyeonhaedok-tang was the largest among the five formulas, regardless of the dosage form. However, since the sample size was too small, these results are not conclusive, that is, it was difficult to evaluate which herbal medicine formula was most effective from our data. Further clinical trials that directly compare herbal medicine formulas should be conducted; otherwise, indirect comparisons (e.g., network meta-analysis) should be performed in order to answer this question.Minimal clinically important difference (MCID) or minimal detectable change (MDC) in MoCA and MMSE has been reported in various conditions but not in MCI. According to two relevant studies, MCID of MMSE ranged from 1.4 to 3.75 points in AD [33, 34]. Another study concluded that MCID of MoCA was estimated as 1.22 or 2.15 points by different methods in stroke patients [35]. A relatively recent study concluded that MDC in MoCA and MMSE was 4 and 3 points, respectively, in participants aged 55 or older without severe cognitive impairment [36]. Considering these, 2.77 and 2.19 points of change in MoCA-K and MMSE-DS scores, respectively, in the entire sample may be interpreted within the clinically meaningful range. To our best knowledge, no MCID information was reported for the full or short-form version of GDS.There are concerns that the practice effect due to repetition of cognitive assessments may affect the results. A validation study of the original MoCA reported that the mean change in MoCA scores within 5 weeks (35.0 ± 17.6 days) was 0.9 ± 2.5 points [23]. In addition, a validation study of MoCA-K also reported a high correlation between the 4-week interval scores [26]. A literature review indicated that healthy control participants showed a practice effect during cognitive assessments (the score was improved), but MCI patients did not [37]. In contrast with patients with cognitive impairment, there were suspicions of MoCA susceptibility in the healthy older adults between the first and second evaluations [38]. In other words, the mean changes in MoCA and MoCA-K may be less affected by practice effects in patients with MCI. However, the original research team has developed three versions of MoCA to decrease learning effects when MoCA is administered every 3 months or less [39]. Regarding recommendations of experts, our results may be affected by the practice effect on the MoCA-K because the evaluation intervals were less than 3 months. Nevertheless, we thought a 2.77-point change in MoCA-K was higher than the generally expected changes in MoCA considering previous test-retest results [23, 26]. Although our results are not conclusive, these findings can be used as preliminary data, suggesting the possibility of a clinical effect of KSHPP. Further KSHPP and effectiveness studies should be planned to use alternative versions of MoCA to decrease possible practice effects if the duration of the program was 3 months or less. Otherwise, the interval between before and after evaluation should be longer than 3 months.In terms of safety, there were no clinically meaningful changes in the outcomes of LFT and RFT after herbal medicine treatment. There was also no evidence of DILI and drug-induced kidney disease. The participants were older adults, and most suffered from underlying diseases and often took medications. Despite taking additional herbal medicines, there were no cases of adverse events. These findings are consistent with those of previous research on in-patient samples [40–42]. According to a previous study [40] on the safety of herbal medicine administered alone or in combination with conventional medicine, 6 of 313 patients showed abnormal liver function without related clinical symptoms (1.9%). This finding indicates that herbal drugs are relatively safe when used alone (0% of 57 patients), but the risk of adverse reactions may increase when herbal and conventional drugs are taken concurrently (2.3% of 256 patients). During the concurrent use of herbal medicine and conventional medicine, the prevalence of DILI was 5 out of 892 (0.56%) [41]. In addition, a retrospective large-sample cohort study of musculoskeletal disorder patients who took traditional herbal medicine showed that the prevalence of liver injury in patients with normal liver function was 27 out of 4769 (0.6%). A total of 354 patients had liver injuries at the time of admission (5.1%) and 217 at the time of discharge (3.1%). Only 9 showed a clinically significant increase after herbal medicine intake; 225 recovered to the normal range or showed significant liver function recovery. Herbal medicine did not exacerbate liver injury in most patients [42]; in other words, herbal medicine is relatively safe.Our main findings were that 130 (26.0%) of 500 patients with MCI were depressed, and herbal medicine and acupuncture were effective treatments for MCI and geriatric depression. Several studies have shown that depression in late life presents with pseudodementia as a core symptom, but it also acts as a risk factor for MCI and dementia [43–45]. A previous study reported that the prevalence of depression among the community-dwelling population with MCI was 25%, and the comorbidities of depression reached up to 40% in clinical samples of MCI [46]. Although the comorbidity rate of mild cognitive impairment associated with major depressive disorder is high, mixed results have been reported so far on the cognitive improvement induced by cholinesterase inhibitors in patients [47, 48]. Another study reported that the combination of donepezil, a cholinesterase inhibitor, and an antidepressant could improve cognitive function but worsen the depressive state [49]. In other words, in the management of patients with mild cognitive impairment, conventional drug treatment is limited, and there are more limitations when depression, as well as cognitive dysfunction, is comprehensively managed.In contrast, Korean medicine has the advantage of using the same herbal prescription and acupoint for cognitive decline and depression. For example, Guibi-tang (also called Guipi-tang in Chinese and Kihito in Japanese) and modified Guibi-tang showed effectiveness compared with monotherapy when combined with conventional medication to treat AD [50] and depression [51]. Recently, the pharmacological activities and the molecular mechanisms of several herbal formulas have been studied to examine their potential effects on cognition and depression [52]. In addition, acupuncture is a common nonpharmacological intervention widely used to treat depression [53] and cognitive impairment [8–11]. GV20, EX-HN1, EX-HN3, LI4, PC6, ST36, and LR3 are acupoints widely used in acupuncture for MCI and depression [54–56]. Functional magnetic resonance imaging (fMRI) studies have been used to investigate neuronal mechanisms of acupuncture to provide a foundation for treating depressive disorder [57, 58] and MCI [54]. Further research for exploring the underlying mechanisms of the effects of herbal medicine and acupuncture on both MCI and depression should continue.The present study has several limitations. First, because this is a retrospective study, there were missing data, which may have resulted in selection bias. Second, there was no control group. We could not assess the efficacy of herbal medicine and acupuncture in comparison with placebo or sham. Moreover, as the intervention groups were classified retrospectively, we did not compare the intervention groups. We did not use a stratified matching because the sizes of the herbal extract and acupuncture groups were relatively small. However, we tried to show the effect of each subgroup according to the type of treatment. Third, as we did not restrict the qualifications of practitioners and provide standardized criteria for pattern identification, the free choice in prescribing herbal medicine formulas may be a concern. As we did not investigate their expertise and experience in Korean medicine, we could not discuss the impact of this on the effects of herbal medicine treatments. Fourth, because the reassessment was mostly conducted within 3 months, there may have been a practice effect resulting from repeated measurements. A previous study concluded that screening instruments, such as MMSE, are highly prone to practice effects in healthy older adults and those diagnosed with dementia at retest intervals of 3 months [59]. Finally, we could not determine the long-term effects of KSHPP based on this study. The long-term effect is especially important in MCI because MCI has a risk of conversion to dementia (particularly AD), and AD is a degenerative and progressive disorder [2]. For participants, a further program should be planned to increase the duration of treatment and consider long-term follow-up. Because of these limitations, the results of this study should be generalized with caution. We need more rigorous clinical trials with longer durations of treatment and long-term follow-up to produce more concrete evidence on the efficacy and effectiveness of herbal medicine and acupuncture. If the time-intervals between assessments and reassessments would not be long enough, it may be better to use alternate forms of MoCA to eliminate practice effects [60].


## 5. Conclusions

Our findings suggest that community-dwelling older adults with MCI have risks of geriatric depression, and Korean medicine interventions, such as herbal medicine and acupuncture, can improve cognitive dysfunction and depression symptoms in MCI. In addition, herbal medicine prescribed by doctors of Korean medicine was safe, based on liver and renal function tests. However, as there were limitations in this study, particularly study design, practice effect, and short follow-up; these results should be interpreted with caution. We need a further long-term study with a rigorous design to retain confidence in the effectiveness and safety of KSHPP.



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