1 Background
It is estimated that more than 300 million people worldwide suffer from major depressive disorder (MDD) [
1], and that by 2020, major forms of depression will become the second leading cause of global disease burden after ischemic heart disease [
2]. Depression is a current public health concern because of its early-age of onset, high prevalence, high impact on patient quality of life and ability to function, as well as high clinical and economic burden [
3]. Depression can occur at any point during an individual’s lifetime and is characterized by a single or recurrent episode of clinically diagnosed depressive symptoms with variations during each episode. It is the most common severe psychiatric illness and affects emotions, thought, and behavior, leading to low disease-related quality of life. The incidence of suicide attempts is about 20- to 40-fold for patients suffering from an MDD episode [
4], making suicide the second leading cause of death among 15- to 29-year-olds globally [
5]. Japan has one of the highest suicide rates worldwide [
6].
Although depression can be treated pharmacologically, studies in the USA [
7] and UK [
8] reported that a substantial subset of depression patients, termed treatment-resistant depression (TRD) patients, do not achieve an adequate clinical response to the administration of antidepressants. The current definition of TRD lacks consensus; however, the Committee for Medicinal Products for Human Use at the European Medicines Agency defines TRD as pharmacologically-treated depression (PTD) that does not show clinically meaningful improvement after at least two different antidepressant medications used for a sufficient length of time at an adequate dose with adequate affirmation of treatment adherence [
9].
Large longitudinal studies suggest that MDD patients who develop treatment resistance have a low chance to achieve response or remission with each subsequent line of treatment [
10]. Although TRD patients have been characterized well in regard to their clinical characteristics, including co-morbidities, there is a paucity of data with regard to the epidemiological and health economic consequences in Japan. Furthermore, the burden of TRD in terms of disability, cost, human suffering and suicide is unclear [
11] because the accurate and systematic assessment of TRD, including predictive utility and reliability of TRD staging, is difficult [
12]. Usually, response is defined as a reduction in depressive symptoms to < 50%, and remission as a full recovery [
13].
From a US economic viewpoint, patients with TRD generate higher direct medical costs compared with those with MDD within a 12-month time horizon [
14] and have higher indirect productivity costs from a societal point of view [
15]. One reason for this difference in economic burden is the increased number of co-morbidities in TRD patients compared with non-TRD patients [
16]. In addition, secondary administrative data indicated that some patients are treated with up to four different pharmacological treatments still fail to respond to treatment, and thus have higher healthcare utilization and higher per-patient medical costs [
17].
The estimated lifetime prevalence of MDD in the USA is 16.2% [
18], and the 12-month prevalence is 6.7% [
19]. Estimations about the rate of patients developing TRD vary widely from 6.6 [
7] to 35% [
20] of MDD patients. For Japan, the lifetime and 12-month prevalence rates of MDD were estimated as 3–7 and 1–2%, respectively [
21]. Interestingly, patients with depression in Japan were reported to be less likely to seek medical treatment or consult a psychiatrist compared with patients in Western countries [
21], and the lack of utilization of mental health services was not related to gender, age or income level. Furthermore, an international WHO report indicated that in Japan the majority of people recently diagnosed with a psychiatric disorder do not seek mental healthcare or use other support systems [
22]. However, no longitudinal cohort studies are available for Japan that would allow a good estimation of TRD rates and related costs. The aim of this study was therefore to estimate the incidence, the amount of medical services used, and the direct costs of PTD and TRD, through a retrospective analysis of a health insurance claims database and thus help improve our understanding of the socioeconomic impact of TRD in Japan.
2 Methods
2.1 Data Source
Health insurance claims data from non-governmental employees and their family members between July 2009 and March 2015 sourced from multiple health insurance associations were retrieved from the Japan Medical Data Center (JMDC). During this period, a total of 2,958,220 patients were enrolled in the JMDC database. The database provides comprehensive patient and clinical information, including patient demographics, diagnostic codes, dates and types of procedures, dispensed prescription drugs, medical services provided to inpatients and outpatients, and expenditures. The JMDC database has been used to investigate a wide range of conditions in Japan such as schizophrenia [
23] or cardiovascular disease [
24]. All personally identifiable information was de-identified to protect patient privacy. Therefore, no informed consent was necessary.
2.2 Selection of Study Population
A retrospective cohort design was used. JMDC database members joined the study cohort on 1 April 2012 if they were within 18–60 years of age (i.e., were born between 1952 and 1994), had no prior depression diagnosis (ICD 10; F32.x, F33.x, F34.1, F41.2, F43.2, F53.0), no previous diagnoses of other mental diseases (ICD 10; F0;F1;F2;F3F20; F30;F31), and no prior prescription of any antidepressant medication before 31 March 2012. Antidepressant medication was defined as a medication that is approved for the treatment of depression in Japan. The list of antidepressant medications can be found in Supplementary Table
1. Patients were censored if they develop other psychiatric conditions as mentioned above after they were included in the study cohort.
Table 1
Selection of subjects
All database members | 2,958,220 |
Born between 1952 and 1994 | 2,092,248 |
Continuously enrolled between Dec 2011 to Mar 2012 | 130,339 |
Do not have depression diagnosis or antidepressant medication dispensing before Mar 2012 | 101,357 |
No exclusion diagnosis before Mar 2012 | 101,006 |
Database member after Apr 2012 eligible for study cohort | 98,552 |
Based on these criteria, 98,552 patients who were continuous JMDC database members from 1 April 2012 through 31 March 2013 were included in this analysis (Table
1). Maximal follow-up time was until 31 March 2015.
2.3 Identification of a Pharmaceutically Treated Depression (PTD)
A pharmaceutically treated depression (PTD) treatment interval began when a study subject received a depression diagnosis and simultaneously or subsequently (within less than 30 days) a dispensation of an antidepressant medication.
The start of a treatment interval was the date of depression diagnosis or the date of antidepressant medication dispensation, whichever was earlier. A treatment interval was terminated when the subject received no depression diagnosis and was dispensed no antidepressant medication for 120 days. The duration of a PTD interval was defined as the number of months from PTD index month to the month a treatment interval ends. It is important to recall that what we call a treatment interval of PTD is a sequence of dispensing of antidepressant medications and visits with a depression diagnosis, and that this represents a treatment interval of care for PTD rather than a clinical episode of clinical depression. In particular, medication may include some prophylaxis.
2.4 Identification of Treatment-Resistant Depression (TRD)
A TRD treatment interval is a PTD treatment interval in which two treatment regimens have failed. A treatment regimen fails when, at least 15 days after it began, an antidepressant medication is added or substituted for another medication. We assumed 15 days as adequate threshold, because evidence suggest that nonresponse is predicted by a lack of symptom improvement during the first 14 days of therapy [
25]. Moreover, this is a common definition used in database analysis and choosing this threshold value allows for a better comparability across database studies [
26].
As we are not able to observe symptom improvements in claims databases, we acknowledge that there is some uncertainty around this definition.
2.5 Resource Utilization
Hospital claims were characterized by resource utilizations as: hospitalization in emergency department, hospitalization in psychiatric emergency department, psychiatric hospitalization, all hospitalizations, psychiatric office visit (out-patient), and office visit (out-patient). Total cost per patient and total cost per patient-year were calculated. Cost per person-time and cost per person capture of different information and the former measure adjusts for time while the latter does not. Total cost refers to the sum of costs paid by insurance and by the patients via co-insurance schemes and that are paid out of pocket. The co-insurance rate is 30% for people under 70 years of age and 20% for those above 70 years of age. Maximum co-payments are capped depending on household income ranging from 35,400 JPY (US$307) per month for the population earning less than 1 million (US$8700) a year to 252,600 JPY per month (US$2200) for those with an annual income above 11.6 million JPY (US$100,900). Once a person turns 70 years old, the upper limit of the co-payments is reduced drastically ranging from 8000 (US$70 USD) to 80,000 JPY (US$700) per month depending on income and whether the cost is related to in-patient or out-patient services. At the age of 75 years, everyone in Japan switches to an insurance scheme for the elderly that was established 2008. The common co-payment rate for this plan is 10% [
27]
2.6 Statistical Analysis
This study employed a cohort design because TRD is defined by a temporal sequence of events (unsuccessful treatment regimens) that may occur in a subject with PTD. A cohort perspective also facilitates estimation of TRD incidence and duration of treatment. This was a descriptive study so no effect measure was calculated. The incidence of PTD and TRD were estimated by proportion per year. Group comparisons were conducted using the Kruskal–Wallis test with post hoc Scheffe’s rank sum multiple contrast tests. All statistical analyses were performed using R version 3.2.1 (The R Foundation for Statistical Computing, Vienna, Austria).
Compliance with Ethical Standards
This was a retrospective database study; the authors were not involved in the collection of this data. Retrieval of the data from this database occurred in an unlinked fashion. As the data had been anonymized, the Ethical Guidelines for Epidemiological Research (Ministry of Education, Culture, Sports, Science and Technology, and Ministry of Health, Labour and Welfare of Japan), which require ethics approval and informed consent, are not applicable to this study. Based on the Ethical Guidelines on Biomedical Research Involving Human Subjects (Ministry of Education, Culture, Sports, Science and Technology, and Ministry of Health, Labour and Welfare of Japan), pharmacoepidemiological studies conducted on medical databases constitute research carried out on pre-existing material and information, that did not require any interventions or interactions with patients. For such studies, including this study, obtaining written informed consent from patients is not compulsory.
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