Acupuncture treatment and the risk of dementia | NDT

Dementia is one of the major causes of disability in old age. It is a condition that is characterized by a decrease in cognition involving one or more cognitive domains (learning and memory, language, executive function, complex attention, perceptual-motor function, social cognition)2,4 As of 2010, there were 35.6 million people with dementia worldwide. The number is predicted to reach 65.7 million in 2030 and 115.4 million in 2050.5 Dementia mainly affects older people, and its prevalence increases exponentially with age. Depression and dementia commonly occur together in elderly people. Recent studies indicate that early-life depression could be a risk factor for later dementia and that later-life depression is a prodrome of dementia.6 These findings show the importance of effective treatment for depression, which may reduce the prevalence of dementia.

Taiwan launched the National Health Insurance (NHI) program in 1995. This compulsory insurance program covers more than 99% of all residents in Taiwan, and it provides universal care to the people of Taiwan. The NHI program began reimbursing Western medical services in 1995 and traditional Chinese medicine (TCM) services in 1996. The NHI administration has established a National Health Insurance Research Database (NHIRD), which includes all claims data. These datasets provided real-world data with long-term follow-up information, reducing the potential for sampling bias.19 Our previous studies have also shown that acupuncture treatment is beneficial for patients with fibromyalgia,20,21 arthritis,22,23 and depression24 in the NHIRD. As recently noted, “real-world” data are not inferior to clinical trials and may provide useful information.25 Due to the shortage of existing long-term follow-up studies, our study aims to determine whether acupuncture can decrease the risk of progression to dementia in patients with depression by using a random sample of one million patients selected from the NHIRD.

The data in this study are selected from the Taiwanese NHIRD (https://nhird.nhri.org.tw/en/), which contains the registration files and original claims data for reimbursements, including demographic characteristics, diagnoses, clinical visits, hospitalizations, procedures, prescriptions, and the medical costs for reimbursement; this information is provided to scientists in Taiwan for research purposes. The NHI program covers TCM services, including Chinese herbal medicine, manipulative therapies and acupuncture. The diagnostic codes follow the format of the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM).

The flowchart for enrolling patients with depression and dementia is shown in Figure 1. A sample of one million randomly selected individuals from the NHIRD database was used in this study. Patients (n = 65,569) with diagnosed depression (ICD-9-CM code: 296.2–296.3, 300.4, 311) between January 1997 and December 2010 were included in this study and then followed up until the end of 2013. Next, we narrowed the selection to patients who were newly diagnosed with depression between 1997 and 2010 and had at least 2 claims during that period. We excluded 1840 individuals who were younger than 18 years of age or who had missing information such as date of birth or sex. In addition, we excluded 3343 individuals whose date of dementia diagnosis (ICD-9-CM: 290, 294.1, 331.0–331.2) was before the date of depression diagnosis. In all, after these exclusions, there were 49,993 patients with newly diagnosed depression and at least 2 claims during the period from 1997 to 2010. The remaining patients were divided into two groups: those who received acupuncture treatment (n =23,149) and those who did not (n=26,844). We defined the date of first acupuncture treatment after the date of the new depression diagnosis as the index date for the acupuncture group, and we randomly chose a date between the date of the new depression diagnosis and the endpoint as the index date for the control group. The acupuncture treatment (n =16,609) group and the control (n=16,609) group were matched 1:1 for propensity score by age (in 5-year bins), sex, index year, initial year of diagnosis of depression, all comorbidities, and all drugs used (oral steroids; nonsteroidal anti-inflammatory drugs (NSAIDs); statins; and selective serotonin reuptake inhibitors (SSRIs: escitalopram, fluvoxamine, sertraline), monoamine oxidase inhibitors (MAOIs: selegiline, isocarboxazid, tranylcypromine, phenelzine, moclobemide), tricyclic antidepressants (TCAs: amoxapine, desipramine, imipramine, doxepin, clomipramine, trimipramine) and other antidepressant drugs (serotonin–norepinephrine reuptake inhibitors, SNRIs: venlafaxine, duloxetine, milnacipran; norepinephrine–dopamine reuptake inhibitor, NDRI: bupropion; serotonin antagonist and reuptake inhibitor, SARI: mesyrel; noradrenergic and specific serotonergic antidepressant, NaSSA: mirtazapine)) (Figure 1).

Figure 1 Flow chart of the selection of patients with depression from the National Health Insurance Research Database (NHIRD) between 1997 and 2000 in Taiwan. After excluding the patients who did not meet the inclusion criteria and matching by propensity score, the acupuncture and non-acupuncture cohorts each contained an equal number of patients.

The investigation was carried out in accordance with the latest version of the Declaration of Helsinki. The National Health Research Institutes encrypted all information that could be used to identify individuals or care providers before release; it is therefore impossible to identify any individuals or care providers in the database. The Research Ethics Committee of China Medical University and Hospital approved this study and waived the requirement for informed consent (CMUH104-REC2-115).

The datasets analyzed from NHIRD were provided by the National Health Insurance Administration and maintained by the National Health Research Institutes of Taiwan. The use of NHIRD is limited to research purposes only. Applicants must follow the Computer-Processed Personal Data Protection Law (http://www.winklerpartners.com/?p=987) and related regulations of the National Health Insurance Administration and National Health Research Institutes.

In addition, there was a significant relationship between the risk of dementia and whether drugs were used to treat depression after diagnosis. Compared to the group who did not use drugs, the patients who used SSRIs, MAOIs and TCAs had an elevated aHR (1.09, 1.47 and 1.1). This may be because patients who used these antidepressants initially had more severe depression than those who did not take them. However, the patients who used oral steroids, NSAIDs, statins and other antidepressant drugs had reduced aHRs (0.53, 0.20, 0.56 and 0.71).

In this study, 1071 patients in the acupuncture cohort (12.11 per 1000 person-years) and 1436 patients in the non-acupuncture cohort (19.68 per 1000 person-years) developed dementia (Table 3). The beneficial effect of acupuncture on the incidence of dementia was noted in both female and male patients (female aHR, 0.53; 95% CI, 0.48–0.58; male aHR, 0.56; 95% CI, 0.49–0.63). Although the risk of dementia gradually increased with age, acupuncture significantly decreased the progression of dementia in all age groups. Acupuncture decreased the risk of dementia in patients with depression with and without comorbidities (diabetes mellitus, hypertension, hyperlipidemia, congestive heart failure, anxiety, alcoholism, tobacco use, and obesity). Regardless of whether patients took oral steroids; NSAIDs; statins; or SSRIs, MAOIs, TCAs and other antidepressant drugs, fewer patients in the acupuncture cohort than in the non-acupuncture cohort developed dementia.

Table 4 Incidence Rates, Hazard Ratio and Confidence Intervals of Vascular Dementia (ICD-9-CM: 290.4) and Alzheimer’s Disease (ICD-9-CM: 331.0) for Those Depression Patients Who Received Acupuncture and Those Who Did Not, Stratified by Sex, Age, Comorbidities and Drug Use

Figure 2 Cumulative incidence of dementia between the acupuncture cohort and the non-acupuncture cohort. The cumulative incidence of dementia was significantly lower in the acupuncture cohort than in the non-acupuncture cohort (Log rank test, p < 0.0001).

A previous study using resting-state functional magnetic resonance imaging (RS-fMRI) found that acupuncture stimulation could modulate the activity of the default mode network in Alzheimer’s disease patients.34 Another fMRI study indicated that acupuncture could improve hippocampal connectivity in Alzheimer’s disease patients.35 It was also found that the right hemisphere (the temporal lobe, such as the hippocampal gyrus; the insula; and some areas of the parietal lobe) and left hemisphere (the temporal lobe, the parietal lobules, and some regions of the cerebellum) were activated after acupuncture therapy. The regions activated by acupuncture overlap with the areas of the brain that are impaired in Alzheimer’s disease patients.36

It has to be point out that our research also has some limitations. First, the NHIRD did not provide data to measure the severity of depressive disorders. To minimize this confounding factor, we performed 1:1 propensity score matching to ensure that all the baseline characteristics of both cohorts (including the anti-depressants) were similar. Second, the lifestyles of the two cohorts could be different. The NHIRD did not provide data about patients’ lifestyles, such as smoking frequency, body mass index (BMI), stress, and exercise. Studies have indicated that many dementia cases are attributable to risk factors such as obesity, physical inactivity, and smoking.40 Since data on lifestyle factors were deficient, we had only a limited ability to study these personal habits and customs in connection with illness. We performed 1:1 propensity score matching including the diagnoses of tobacco use and obesity and found that the comorbidities of both cohorts were similar. However, the percentages of smoking and obesity were still underestimated in both cohorts. Third, patients who seek acupuncture may have an increased level of motivation to address depression. Although the co-pay of acupuncture therapy is low (5–7 USD per treatment) under the NHI program, it is still a burden for poor people to consult doctors frequently. Thus, acupuncture users may have greater financial ability to obtain tangible or intangible resources than non-users.

Data Sharing Statement

The datasets we used in this study were released by the Taiwan NHIRD (https://nhird.nhri.org.tw/en/), maintained and managed by National Health Research Institutes (http://www.nhri.org.tw/), Taiwan. The datasets are limited to be used for research purposes only. Applicants must follow the Computer-Processed Personal Data Protection Law (http://www.winklerpartners.com/?p= 987) and related regulations of National Health Insurance Administration and National Health Research Institutes, and the agreement must be signed by the applicant and his/her supervisor upon application submission. All applications are reviewed for approval of data release.

Author Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. Mei-Yao Wu and Hung-Rong Yen contributed equally as co-corresponding authors.

This work was financially supported by the Chinese Medicine Research Center, China Medical University, from the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan (CMRC-CHM-2). This study was also partially supported by China Medical University (CMU103-BC-4-2, CMU105-BC-1-1, CM105-BC-1-2); the health and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW110-TDU-B-212-144024), Taiwan; the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW110-TDU-B-212-124004). None of the funders and institutions listed had a role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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