Retrospective cohort study.

This study is based on the NDB managed by the Ministry of Health, Labor and Welfare (permission no. 0710-4). The NDB is one of several government-maintained nationwide healthcare-related databases in Japan. All residents of Japan are covered by the public health insurance, and thus the database includes data on all the drugs prescribed in Japan.

Okayama, Hiroshima, and Ehime prefectures were selected as the target areas for the location of medical institutions, where the damage was concentrated as described in the introduction. The survey period was set between July 2017 and June 2019, which is a period of 1 year before the disaster and 1 year after the disaster. The subjects of this study were those who were 65 years old or older and visited and were issued health insurance claims from medical institutions located in Okayama, Hiroshima, and Ehime prefectures among the registrants in the database. Among the subjects, those who were identified as disaster-victims by the local government were also considered as disaster-victims in this study. The rest of the participants were identified as non-victims and analyzed separately.

During the 2018 Japan Floods, it was announced by the Japanese government that medical insurance co-payments would be fully exempted for victims (14). We therefore defined a “disaster-victim” as a person who was listed as a disaster-victim in the special notes on health insurance claims issued after the disaster. However, people whose medical expenses had been already funded by the government, such as livelihood recipients and atomic bomb survivors who were provided with an atomic bomb survivor's certificate, were not eligible for exemption due to the disaster, therefore were categorized as non-victims even if they were affected.

Government-certified victims were fully exempted from the general out-of-pocket charge (10–30% of the total medical expense) for any medical services and were enrolled as such in the NDB. A disaster-victim was certified by the local government in their residential municipality. The criteria for a certified “disaster-victim” fell into one of the following categories: (1) residential house was completely or partially destroyed, burned down, flooded above the floor level, or similarly damaged, (2) family member who had financially supported the person was killed or suffered severely, or was missing.

Regardless of whether a participant was affected by the disaster or not, YKS was the fourth most commonly prescribed Kampo drug both before and after the disaster (4.9–5.3%) (Supplementary Figures 1A,B), and it was the most commonly prescribed antipsychotic Kampo drug (27.3–28.6%) (Supplementary Figures 1C,D). Moreover, among 39 Kampo drugs approved by the Japan's Ministry of Health, Labor and Welfare to improve psychological symptoms, YKS is the only Kampo drug whose effectiveness is supported with sound scientific evidence (15, 16). For these reasons, we chose YKS as the subject of our analysis.

Micro analysis: The month when the new prescription of YKS was issued for the subjects was identified within the period of the study. Similarly, the month when the new prescription of other Kampo drugs was issued for the subjects was identified. Data on whether the subject was affected by the disaster, age, and gender were also extracted. However, those who had received prescriptions of any Kampo drugs before the disaster were excluded. For age categories and gender, we adopted the numbers on the first health insurance claims within the period of the study.

Aggregate analysis: In the subjects, we counted the number of people who received a prescription of YKS during the period of the study for 1 year before and after the disaster respectively. Likewise, the number of people who received prescriptions of any of 147 Kampo drugs other than YKS was also counted.

Using micro analysis, we quantitatively examined the extent to which the disaster increased the incidence of new prescriptions of YKS and other Kampo drugs. Aggregate analysis was used to compare the change in the magnitude of increase in the number of people prescribed between YKS and other Kampo drugs before and after the disaster. The magnitude of increase was calculated for all subjects for 1 year before and 1 year after the disaster. The difference was examined by a proportion test.

The need for informed consent was obviated by the anonymity of the NDB. This study was permitted by the institutional review board of Hiroshima University (No. E-1688).

The subjects were extracted by restricting the sample to those who had not received any prescriptions of the 148 Kampo drugs in 1 year prior to the disaster. The demographics of those subjects are presented in Table 1. The total number of participants aged 65 years old or more was 1,372,417, and 0.93% were disaster-victims (12,787 people). Participants in their seventies were relatively more affected compared to the other age categories (p < 0.001).

The percentage of all participants by gender was 44.28% male and 55.72% female, which was similar to the percentage of males and females of the same age categories who lived in Okayama, Hiroshima, and Ehime prefectures (42.71 and 57.29%, respectively) as of January 2018 (17). A gender difference in the degree of disaster vulnerability was not observed (p = 0. 822).

Of the three prefectures, Okayama prefecture was the most common location of the medical institutions visited by victims, accounting for 45.95%. The test results showed that the probability of being affected by the disaster was significantly higher for participants who visited medical institutions in Okayama prefecture compared to the other two prefectures (p < 0.001).

The number of victims newly prescribed for YKS amounted to 125 (0.98% of all victims), while non-victims amounted to 8,913 (0.66% of all non-victims). The proportion of new prescriptions of YKS for the disaster-victims was significantly higher than for non-victims (p < 0.001).

The number of disaster-victims prescribed for other Kampo drugs amounted to 1,981 (15.49% of all victims), while non-victims amounted to 161,935 (11.91% of all non-victims). The proportion of new prescriptions of other Kampo drugs for victims was significantly higher than for non-victims (p < 0.001).

Kaplan-Meier failure curves for the patients newly prescribed YKS and other Kampo drugs are shown in Figure 1. As a result of a series of log-rank tests, new prescriptions of YKS (Figure 1, left panel) occurred at a higher rate in disaster-victims compared with non-victims (p < 0.001) and was concentrated in the 2 months after the disaster. We also estimated new prescriptions of other Kampo drugs using the same method (Figure 1, right panel). New prescriptions were observed more frequently among victims than non-victims, which was similar to the results for YKS (p < 0.001). In the contrast to YKS, however, a concentration of new prescriptions for other Kampo drugs at a specific time point was not observed.

Table 2A shows the results of an examination of new prescriptions for YKS using a Cox proportional hazards model. The hazard ratio (HR) for the disaster in the crude model was 1.49 (95% confidence intervals (CI): 1.25–1.78), while that of the adjusted model adjusted by age categories and gender was 1.54 (95% CI: 1.29–1.84), which indicated that the probability of new prescriptions of YKS had increased due to the disaster. We also examined the results by age categories. HR for the age group 70–74 was 1.90 (95% CI: 1.72–2.10), age group 75–79 was 3.57 (95% CI: 3.25–3.92), and age group more than 80 was 8.35 (95% CI: 7.69–9.08), which indicated that YKS was more likely to be prescribed for higher age categories. On the other hand, HR for the disaster in the crude model for other Kampo drugs was 1.33 (95% CI: 1.27–1.39), where the adjusted model was 1.32 (95% CI: 1.27–1.38), both of which were >1 as well as for YKS (Table 2B). Although the 95% CI for YKS and other Kampo drugs slightly overlapped, HR for YKS tended to be greater than the other Kampo drugs.

When the target population was expanded to include all people regardless of whether or not they had been prescribed Kampo before the disaster, the total number was 1,812,373, of which 16,396 were victims (Table 3). The number of patients who were prescribed YKS before and after the disaster was 226 and 297, respectively, and the magnitude of increase (31.4%) was significantly greater than that of other Kampo drugs (19.3%) (p < 0.001). In other words, the impact of the disaster on prescriptions was greater for YKS.

The 2018 Japan Floods increased prescriptions of both YKS and other Kampo drugs among elderly victims. The degree of increase in opportunities for prescribing YKS was greater than that of other Kampo drugs. Supported by the hazard model estimation adjusted for age and gender, these results were confirmed to be robust. The new prescriptions of YKS in victims were most frequently observed 2 months after the disaster. And YKS was more likely to be prescribed for higher age categories. These two characteristics were not observed in other Kampo drugs. Both YKS and other Kampo drugs were more likely to be prescribed for females, but YKS tended to be prescribed more often regardless of gender. To the best of our understanding, this is the first cohort study to quantitatively examine the impact of natural disasters on the prescriptions of Kampo.

The locations of the medical institutions where the affected study subjects visited were, in order of the number of subjects, Okayama, Hiroshima, and Ehime prefectures. This ranking was the same as the ranking of the amount of damage: 421 billion yen/3.89 billion dollars for Okayama, 339 billion yen/3.13 billion dollars for Hiroshima, and 170 billion yen/1.57 billion dollars for Ehime prefecture.

“Yokukansan” means to adjust the function of “kan,” meaning “liver” in Japanese. However, in terms of Kampo medicine, “liver” does not mean “liver” as described in Western medicine. The naming indicates a concept that includes various functions such as emotion, autonomic nervous function, function of the eyes and muscles, and regulation of blood distribution. In other words, YKS has the effect of suppressing mental tension, especially persistent anger caused by dysfunction of the “liver,” hence its name (18).

In times of disaster, the Kampo that are prescribed for psychiatric symptoms as represented by YKS are safe and convenient to use when persons are dealing with an unusual and unfamiliar living environment, such as an evacuation center, because they do not have side effects such as undifferentiated dizziness as often experienced with antipsychotics. However, it is noted that although it contains a relatively small amount of glycyrrhiza (1.5 g/day), it is important to pay attention to its possible side effect of pseudohyperaldosteronism (19).

This study is the first to describe a change in prescriptions of YKS using completely covered data, such as health insurance claims. Japan has a universal health insurance system, which covers almost all medical practices for all residents in the country. Therefore, we were able to quantitatively measure the impact of the disaster in a manner that was close to completely covered for those that had been prescribed YKS at the doctor's discretion. In addition, the data is highly accurate because it is based on a database managed by the government.

Our study has several limitations. We were not able to examine the symptoms of individual patients and efficacy of YKS. Furthermore, medical institutions were not categorized in terms of size, department, whether or not the doctors were Kampo specialists, the content of the medical services, and accessibility. Lastly, in this study, the victims were identified based on the data from health insurance claims. However, it is presumed that there were a certain number of people who were affected, but had not applied for certification as a disaster-victim. In other words, the non-victims in this study might have included people who were affected by the disaster, and the results obtained from this study may be lower than the actual estimates.