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Estimating Prevalence and Healthcare Utilization for Treatment-Resistant Depression in Japan: A Retrospective Claims Database Study

Estimating Prevalence and Healthcare Utilization for Treatment-Resistant Depression in Japan: A... Drugs - Real World Outcomes (2018) 5:35–43 https://doi.org/10.1007/s40801-017-0126-5 ORIGINAL RESEARCH ARTICLE Estimating Prevalence and Healthcare Utilization for Treatment- Resistant Depression in Japan: A Retrospective Claims Database Study 1,2 1 3 • • Jo ¨ rg Mahlich Sunny Tsukazawa Frank Wiegand Published online: 28 November 2017 The Author(s) 2017. This article is an open access publication Abstract million JPY (0. 540 million JPY) in the TRD population Background Major depressive disorders (MDDs) including and 0.643 JPY million JPY (0.645 million JPY) in the PTD treatment-resistant depression (TRD) are common dis- population who did not convert into TRD. abling conditions, but data on their epidemiology in Japan Conclusions This study describes the PTD and TRD are limited. This study investigated the incidence, epi- patient populations in a large claims database in Japan and demiology, and direct medical costs of TRD and pharma- highlights an unmet medical need for the treatment of TRD ceutically-treated depression (PTD) in Japan to increase to provide better preventative measures and interventions our health economic understanding of this phenotype of for the treatment of depression. MDD. Methods A retrospective cohort study from a private health insurance claims database estimated the 1-year Key Points incidence of PTD and TRD and described the health ser- vices used and direct medical costs associated with these This is the first database study to explore prevalence conditions. and associated healthcare utilization and treatment Results In the year from 1 April 2012 through 31 March costs of treatment-resistant depression in Japan. 2013, we identified 1143 incident PTD cases among 98,552 Our findings suggest that patients suffering from eligible subjects, i.e. 11.59 cases/1000 patient-years. Of the treatment-resistant depression cause higher PTD patients, 51.4% were women. Within the 1-year healthcare costs per episode compared with patients observation interval 137 patients failed more than two with depression that is not treatment resistant. antidepressive treatment approaches and thus developed TRD. Though co-morbid conditions and age were similar among PTD and TRD patients, medical costs per patient (patient-year) during their treatment intervals were 1.01 1 Background Electronic supplementary material The online version of this It is estimated that more than 300 million people world- article (https://doi.org/10.1007/s40801-017-0126-5) contains supple- mentary material, which is available to authorized users. wide suffer from major depressive disorder (MDD) [1], and that by 2020, major forms of depression will become the & Jo¨rg Mahlich second leading cause of global disease burden after joerg.mahlich@gmail.com ischemic heart disease [2]. Depression is a current public health concern because of its early-age of onset, high Health Economics, Janssen Pharmaceutical K.K, 5-2, Nishi- kanda 3-chome, Chiyoda-ku, Tokyo 101-0065, Japan prevalence, high impact on patient quality of life and ¨ ability to function, as well as high clinical and economic Dusseldorf Institute for Competition Economics (DICE), University of Du¨sseldorf, Du¨sseldorf, Germany burden [3]. Depression can occur at any point during an individual’s lifetime and is characterized by a single or Janssen Global Services LLC, Raritan, NJ, USA 36 J. Mahlich et al. recurrent episode of clinically diagnosed depressive were estimated as 3–7 and 1–2%, respectively [21]. Inter- symptoms with variations during each episode. It is the estingly, patients with depression in Japan were reported to most common severe psychiatric illness and affects emo- be less likely to seek medical treatment or consult a psy- tions, thought, and behavior, leading to low disease-related chiatrist compared with patients in Western countries [21], quality of life. The incidence of suicide attempts is about and the lack of utilization of mental health services was not 20- to 40-fold for patients suffering from an MDD episode related to gender, age or income level. Furthermore, an [4], making suicide the second leading cause of death international WHO report indicated that in Japan the among 15- to 29-year-olds globally [5]. Japan has one of majority of people recently diagnosed with a psychiatric the highest suicide rates worldwide [6]. disorder do not seek mental healthcare or use other support Although depression can be treated pharmacologically, systems [22]. However, no longitudinal cohort studies are studies in the USA [7] and UK [8] reported that a sub- available for Japan that would allow a good estimation of stantial subset of depression patients, termed treatment- TRD rates and related costs. The aim of this study was resistant depression (TRD) patients, do not achieve an therefore to estimate the incidence, the amount of medical adequate clinical response to the administration of antide- services used, and the direct costs of PTD and TRD, pressants. The current definition of TRD lacks consensus; through a retrospective analysis of a health insurance however, the Committee for Medicinal Products for claims database and thus help improve our understanding Human Use at the European Medicines Agency defines of the socioeconomic impact of TRD in Japan. TRD as pharmacologically-treated depression (PTD) that does not show clinically meaningful improvement after at least two different antidepressant medications used for a 2 Methods sufficient length of time at an adequate dose with adequate affirmation of treatment adherence [9]. 2.1 Data Source Large longitudinal studies suggest that MDD patients who develop treatment resistance have a low chance to Health insurance claims data from non-governmental achieve response or remission with each subsequent line of employees and their family members between July 2009 treatment [10]. Although TRD patients have been charac- and March 2015 sourced from multiple health insurance terized well in regard to their clinical characteristics, associations were retrieved from the Japan Medical Data including co-morbidities, there is a paucity of data with Center (JMDC). During this period, a total of 2,958,220 regard to the epidemiological and health economic conse- patients were enrolled in the JMDC database. The database quences in Japan. Furthermore, the burden of TRD in terms provides comprehensive patient and clinical information, of disability, cost, human suffering and suicide is unclear including patient demographics, diagnostic codes, dates [11] because the accurate and systematic assessment of and types of procedures, dispensed prescription drugs, TRD, including predictive utility and reliability of TRD medical services provided to inpatients and outpatients, and staging, is difficult [12]. Usually, response is defined as a expenditures. The JMDC database has been used to reduction in depressive symptoms to\50%, and remission investigate a wide range of conditions in Japan such as as a full recovery [13]. schizophrenia [23] or cardiovascular disease [24]. All From a US economic viewpoint, patients with TRD personally identifiable information was de-identified to generate higher direct medical costs compared with those protect patient privacy. Therefore, no informed consent with MDD within a 12-month time horizon [14] and have was necessary. higher indirect productivity costs from a societal point of view [15]. One reason for this difference in economic 2.2 Selection of Study Population burden is the increased number of co-morbidities in TRD patients compared with non-TRD patients [16]. In addition, A retrospective cohort design was used. JMDC database secondary administrative data indicated that some patients members joined the study cohort on 1 April 2012 if they are treated with up to four different pharmacological were within 18–60 years of age (i.e., were born between treatments still fail to respond to treatment, and thus have 1952 and 1994), had no prior depression diagnosis (ICD higher healthcare utilization and higher per-patient medical 10; F32.x, F33.x, F34.1, F41.2, F43.2, F53.0), no previous costs [17]. diagnoses of other mental diseases (ICD 10; The estimated lifetime prevalence of MDD in the USA F0;F1;F2;F3F20; F30;F31), and no prior prescription of is 16.2% [18], and the 12-month prevalence is 6.7% [19]. any antidepressant medication before 31 March 2012. Estimations about the rate of patients developing TRD vary Antidepressant medication was defined as a medication widely from 6.6 [7] to 35% [20] of MDD patients. For that is approved for the treatment of depression in Japan. Japan, the lifetime and 12-month prevalence rates of MDD The list of antidepressant medications can be found in Prevalence and Healthcare Utilization for Treatment-Resistant Depression 37 Supplementary Table 1. Patients were censored if they threshold value allows for a better comparability across develop other psychiatric conditions as mentioned above database studies [26]. after they were included in the study cohort. As we are not able to observe symptom improvements in Based on these criteria, 98,552 patients who were con- claims databases, we acknowledge that there is some tinuous JMDC database members from 1 April 2012 through uncertainty around this definition. 31 March 2013 were included in this analysis (Table 1). Maximal follow-up time was until 31 March 2015. 2.5 Resource Utilization 2.3 Identification of a Pharmaceutically Treated Hospital claims were characterized by resource utilizations Depression (PTD) as: hospitalization in emergency department, hospitaliza- tion in psychiatric emergency department, psychiatric A pharmaceutically treated depression (PTD) treatment hospitalization, all hospitalizations, psychiatric office visit interval began when a study subject received a depression (out-patient), and office visit (out-patient). Total cost per diagnosis and simultaneously or subsequently (within less patient and total cost per patient-year were calculated. Cost than 30 days) a dispensation of an antidepressant per person-time and cost per person capture of different medication. information and the former measure adjusts for time while The start of a treatment interval was the date of the latter does not. Total cost refers to the sum of costs paid depression diagnosis or the date of antidepressant medi- by insurance and by the patients via co-insurance schemes cation dispensation, whichever was earlier. A treatment and that are paid out of pocket. The co-insurance rate is interval was terminated when the subject received no 30% for people under 70 years of age and 20% for those depression diagnosis and was dispensed no antidepressant above 70 years of age. Maximum co-payments are capped medication for 120 days. The duration of a PTD interval depending on household income ranging from 35,400 JPY was defined as the number of months from PTD index (US$307) per month for the population earning less than 1 month to the month a treatment interval ends. It is million (US$8700) a year to 252,600 JPY per month important to recall that what we call a treatment interval of (US$2200) for those with an annual income above 11.6 PTD is a sequence of dispensing of antidepressant medi- million JPY (US$100,900). Once a person turns 70 years cations and visits with a depression diagnosis, and that this old, the upper limit of the co-payments is reduced drasti- represents a treatment interval of care for PTD rather than a cally ranging from 8000 (US$70 USD) to 80,000 JPY clinical episode of clinical depression. In particular, med- (US$700) per month depending on income and whether the ication may include some prophylaxis. cost is related to in-patient or out-patient services. At the age of 75 years, everyone in Japan switches to an insurance 2.4 Identification of Treatment-Resistant scheme for the elderly that was established 2008. The Depression (TRD) common co-payment rate for this plan is 10% [27] A TRD treatment interval is a PTD treatment interval in 2.6 Statistical Analysis which two treatment regimens have failed. A treatment regimen fails when, at least 15 days after it began, an This study employed a cohort design because TRD is antidepressant medication is added or substituted for defined by a temporal sequence of events (unsuccessful another medication. We assumed 15 days as adequate treatment regimens) that may occur in a subject with PTD. threshold, because evidence suggest that nonresponse is A cohort perspective also facilitates estimation of TRD predicted by a lack of symptom improvement during the incidence and duration of treatment. This was a descriptive first 14 days of therapy [25]. Moreover, this is a common study so no effect measure was calculated. The incidence definition used in database analysis and choosing this of PTD and TRD were estimated by proportion per year. Table 1 Selection of subjects Criterion Number of patients 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 101,357 dispensing before Mar 2012 No exclusion diagnosis before Mar 2012 101,006 Database member after Apr 2012 eligible for study cohort 98,552 38 J. Mahlich et al. Group comparisons were conducted using the Kruskal– 3.2 Healthcare Utilization and Medical Costs Wallis test with post hoc Scheffe’s rank sum multiple contrast tests. All statistical analyses were performed using 3.2.1 Medication R version 3.2.1 (The R Foundation for Statistical Com- The antidepressant classes most commonly used were selec- puting, Vienna, Austria). tive serotonin reuptake inhibitors (SSRIs) followed by sul- piride instead of serotonin and noradrenaline reuptake 3 Results inhibitors (SNRIs) (Table 4). Sulpiride has been approved for the treatment of depression in Japan (150–300 mg/day dose). 3.1 Incidence and Patient Characteristics It is apparent from the table that patients received more than one antidepression medication simultaneously. For In total, 1143 (1.2%) subjects experienced 1154 PTD example, the second treatment line in the TRD population treatment intervals for the 98,552 patients contained in the consists of 264/137 = 1.92 antidepression medications per selected sample (Table 1). Of the patients who met the patient on average. inclusion criteria for PTD, 11 patients had more than one 3.2.2 Medical Service Utilization treatment interval during the study period (Table 2). If a patient had at least one TRD treatment interval, the patient In all groups, there were few psychiatric emergency hos- was classified as a TRD patient. Reasons for censoring among subjects with PTD but not TRD and among subjects pitalizations and there were none among newly developed with TRD are shown in Table 2. TRD patients. Patients with non-TRD/PTD had more One hundred and thirty-seven patients developed TRD hospitalization days per person years than TRD patients or within 1 year. TRD and non-TRD/PTD patients (i.e., subjects without PTD (3.857 vs. 1.837 vs. 1.715 days/pa- patients with PTD who did not develop TRD) were of a tient-years) (p\0.05), TRD patients had slightly more similar mean age (43.4 and 42.8 years, respectively) psychiatric hospitalization days/person years than non- (Table 3). Among patients with PTD (whether or not they TRD/PTD patients or subjects without PTD (0.895 vs. developed TRD), 556/1143 (48.6%) were male. In contrast, 0.808 vs. 0.010 days/patient-years) (p\0.0001). The number of psychiatric office visits per patient-years among those with TRD, 84/137 (61.3%) were male. TRD treatment intervals had longer durations (mean among TRD patients was much greater than for non-TRD/ PTD patients or subjects without PTD (17.370 vs. 8.528 vs. 22.0 months, median 25.0 months) than did PTD intervals without TRD (mean 11.0 months, median 7.0 months). 0.156 /patient-years) (p\0.0001). The trend was similar but much less pronounced for all office visits (TRD vs. non- TRD/PTD vs. non PTD: 45.537 vs. 37.019 vs. 21.224/pa- Table 2 Incidence of PTD and TRD tient-years) (p\0.0001). For non-PTD patients service uti- Incident PTD between Apr 2012 to Mar 2013 1143 lization is much smaller in all categories (Table 5). PTD episode censored without TRD 1006 Incident TRD 137 3.2.3 Medical Costs Incident TRD episode not censored 94 Incident TRD episode censored 43 Medical costs in millions of yen per patient were 1.014 for Reasons for censoring among subjects with PTD but not TRD those with TRD, 0.643 for those with PTD but not TRD, End of study 705 and 0.327 for the non-PTD population. Expressed in mil- Left database 230 lions of yen per patient-year, the total direct medical cost of Diagnosis of psychosis 39 TRD is 0.540 million yen, and for non-TRD/PTD it was Diagnosis of mania 5 0.645 million yen. This compares to 0.361 million yen for Diagnosis of bipolar disorder 27 the non-PTD group (Table 5)(p\0.0001). The difference Reasons for censoring among subjects with TRD between the cost per patient (which is similar to the cost End of study 94 per treatment interval) and the cost per patient-year stems Left database 27 from the different treatment durations, which are signifi- Diagnosis of psychosis 6 cantly longer in TRD patients. This reduces the cost when Diagnosis of mania 1 reported as cost per time unit. We report both measures Diagnosis of bipolar disorder 9 because for reimbursement decision makers, the cost-per- Diagnosis of dementia 0 patient approach is probably more relevant since this is the kind of cost policy makers need to deal with when it comes AD antidepressants, PTD pharmaceutically-treated depression, TRD treatment-resistant depression to budget allocation decisions. Prevalence and Healthcare Utilization for Treatment-Resistant Depression 39 Table 3 Description of study subjects and depression episodes by depression type, sex, age group, and co-morbidities Characteristic All subjects PTD subjects PTD subjects TRD PTD treatment PTD treatments TRD excl. TRD subjects intervals intervals excl. treatment TRD intervals Number 98,552 1143 1006 137 1154 1016 137 Age (years) Mean 44.7 43.4 43.4 42.8 43.3 43.4 42.8 SD 10.9 10.5 10.6 9.2 10.5 10.6 9.2 Median 46.0 45.0 45.0 44.0 45.0 45.0 44.0 n % n % n % n % n % n % n % Male age groups (years) 47,242 100% 556 100% 472 100% 84 15% 561 100% 477 100% 84 100% 18–29 4254 9.00% 51 9.20% 45 9.50% 6 1.10% 52 9.27% 46 9.64% 6 7.10% 30–39 7050 14.90% 107 19.20% 89 18.90% 18 3.20% 109 19.43% 91 19.08% 18 21.40% 40–49 14,113 29.90% 209 37.60% 171 36.20% 38 6.80% 211 37.61% 173 36.27% 38 45.20% 50–60 21,825 46.20% 189 34.00% 167 35.40% 22 4.00% 189 33.69% 167 35.01% 22 26.20% Female age groups (years) 51,310 100% 587 100% 534 100% 53 100% 593 100% 539 100% 53 100% 18–29 6364 12.40% 91 15.50% 82 15.40% 9 16.98% 92 15.51% 83 15.40% 9 17.00% 30–39 12,645 24.60% 146 24.90% 133 24.90% 13 24.53% 146 24.62% 133 24.68% 13 24.50% 40–49 14,724 28.70% 159 27.10% 140 26.20% 19 35.85% 162 27.32% 143 26.53% 19 35.80% 50–60 17,577 34.30% 191 32.50% 179 33.50% 12 22.64% 193 32.55% 180 33.40% 12 22.60% Age at onset of episode PTD pharmaceutically-treated depression, SD standard deviation, TRD treatment-resistant depression Table 4 Classes of antidepressant medications used to treat PTD and TRD Medication TRD population PTD population without TRD class 1st regimen (n = 137) 2nd regimen (n = 137) 3rd regimen (n = 137) 1st regimen (n = 1016) 2nd regimen (n = 226) (%) (%) (%) (%) (%) SSRI 80 (58.4) 94 (68.6) 94 (68.6) 424 (41.7) 124 (54.9) Sulpiride 64 (46.7) 71 (51.8) 53 (38.7) 309 (30.4) 59 (26.1) SNRI 19 (13.9) 34 (24.8) 38 (27.7) 154 (15.2) 57 (25.2) NaSSA 16 (11.7) 16 (11.7) 19 (13.9) 82 (8.1) 29 (12.8) TrCA 11 (8.0) 23 (16.8) 29 (21.2) 127 (12.5) 35 (15.5) TeCA 3 (2.2) 5 (3.6) 7 (5.1) 17 (1.7) 32 (1.3) Others 12 (8.8) 21 (15.3) 20 (14.6) 56 (5.5) 12 (5.3) Total 205 (149.6) 264 (192.7) 260 (189.8) 1169 (115.1) 319 (141.2) NaSSA noradrenergic and specific serotonergic antidepressant, PTD pharmaceutically-treated depression, SNRI serotonin and noradrenaline reuptake inhibitor, SSRI selective serotonin reuptake inhibitor, TeCA tetracyclic antidepressant, TrCA tricyclic antidepressant, TRD treatment- resistant depression Japan [28]. The estimated differences between Japan and 4 Discussion the USA or other Western countries may be partially due a greater reluctance to report depression among people in the 4.1 Incidence Japanese population than in Western countries. Compared Our study estimated the 12-month incidence of PTD as to Western countries, Japanese patients with depression were reported to have decreased behaviors of seeking any 1.2% for the privately insured population of Japan. Recent epidemiologic studies of community residents reporting the medical treatment or of consulting a psychiatrist (27% sought any; 14% consulted a psychiatrist), which is lower prevalence of major depression according to DSM-IV cri- teria was 1–2% for 12 months and 3–7% for lifetime in than that reported from many Western countries, and 40 J. Mahlich et al. Table 5 Medical services used by people during PTD episodes (with and without TRD) and by people without PTD Subjects with TRD Subjects with PTD but not TRD Subjects without PTD within first year Count (n) 137 1006 97,409 Person years (PY) 257 1003 88,154 Total Total/subject Total/PY Total Total/subject Total/PY Total Total/ Total/PY subject Hosp. days, psychiatric 230 1.679 0.895 810 0.805 0.808 878 0.009 0.010 Hosp days, all 472 3.445 1.837 3869 3.846 3.857 151,220 1.552 1.715 Psy. Emer. Dep., days 0 0.000 0.000 145 0.144 0.145 194 0.002 0.002 Emer. Dep., days 32 0.234 0.125 48 0.048 0.048 2,038 0.021 0.023 Psy. OV 4,464 32.584 17.370 8554 8.503 8.528 13,708 0.141 0.156 OV 11,703 85.423 45.537 37,130 36.909 37.019 1,870,988 19.21 21.224 Total costs 138.900 1.014 0.540 646.600 0.643 0.645 31,862.000 0.327 0.361 (million Yen) Emer. Dep. emergency department, Hosp., any hospitalization, OV any office visit, Psy. Emer. Dep emergency hospitalization to the psycho- logical department, Psy. OV office visit for psychological treatment, PTD pharmaceutically-treated depression, PY patient-year (/1,000 patient- years), TRD treatment-resistant depression Reported values are not age- or gender-adjusted approximately half of that in the USA [28]. Accordingly, 4.2 Medication previous epidemiological studies have shown a lower prevalence of depression in East-Asian countries including Prescription patterns in the study population showed that SSRIs were the most frequently used drugs, similar to the Korea, Japan, and China compared with the West [29]. Findings from the World Mental Health Japan Survey usage reported for six other East-Asian countries (at 40 2002–2003 [21] for instance suggest that the majority of sites) [32]. In contrast, a similar study in the USA reported people with a recent psychiatric disorder did not utilize that SNRIs were most frequently used [7]. mental healthcare or other support systems, despite service Another finding is the wide usage of sulpiride, which improvement over time. Such cross-cultural differences confirms results of previous studies [34]. A Japanese would equate to a higher diagnostic threshold for depres- chart review for instance found that sulpiride was the most frequently prescribed antidepressant with a share of 40.3% sion in East-Asian countries [30, 31]. Presumably, these cultural differences might also influence the gender effects in 367 outpatients with a major depressive disorder [35]. The wide use of sulpiride is somewhat unexpected given on depression. Considering Japan is in the East-Asian sociocultural realm, similar estimates after accounting for the limited evidence of its efficacy in depression. A review of the UK HTA agency NICE in 2011 identified only one sociocultural differences may be anticipated for this study. Similar to the global trend, women exhibited a greater risk clinical trial that found a statistically significant greater than men for depressive disorders in Japan, although age mean change in the 21-item Hamilton Depression Rating and social class distributions were different from other Scale with 150–300 mg sulpiride compared with placebo. countries [32]. Twelve percent of PTD patients developed NICE concluded that due to the small number of studies TRD within a year, which is in the range of estimates from and lack of study quality assessment, the effectiveness of other countries [4, 20, 33]. For Taiwan, which is culturally second-generation antipsychotics in the treatment of major depressive disorder is unclear [36]. Table 4 indicates that close to Japan, this proportion was estimated to be 21% [26]. As we utilized a database whose members include many subjects were receiving more than one medication for depression at a time, and sulpiride may have been used employees and their families, patients with a very severe history of depression might not be able to stay in to augment an antidepressant. In a Japanese clinical trial, this has been recommended as a successful strategy for employment and are therefore under-represented in this sample. This would imply a downward bias of the TRD accelerating antidepressant response [37]. incidence rate. The majority of TRD patients were male in Our results also suggest that more than one antidepres- our analysis, which is in contrast to findings from Taiwan sant medication was prescribed on average, especially in [26] or the USA [7]. Again, the composition of our data- the later treatment lines, although the link between base might be a potential explanation for this finding. polypharmacy and efficacy has not been established [38] Prevalence and Healthcare Utilization for Treatment-Resistant Depression 41 and polypharmacy is not recommended in international and requirement. Moreover, this study only investigated phar- Japanese guidelines. Instead, clinical guidelines recom- macological interventions among patients with depression. mend monotherapy with a second-generation antidepres- The role of non-pharmacological treatments, such as psy- sant for acute-phase treatment [39]. Despite this, only 26% chotherapy, was not investigated here. For that reason, the of Japanese psychiatrists treat patients with monotherapy estimates from this study are likely to be a lower bound for according to a survey by Ueshima et al. [40]. A Japanese the actual disease incidence. On the other hand, psy- claims database analysis of 7,338 Japanese patients with chotherapy is only rarely prescribed in Japan compared to depression also observed various patterns of polypharmacy its wide use in the USA [49]. Another potential limitation [41]. is that claims were used as the basis of defining events for analysis of study. In clinical practice, prophylactic mea- 4.3 Healthcare Utilization and Medical Cost sures of continued antidepressant prescriptions are taken because those that have had episodes of depression are at Some psychiatric service utilization including psychiatric increased risk for sequential episodes [45, 50]. Prophylactic hospital days, overall office visits, and psychiatric office treatment behavior would be indistinguishable from visits for TRD patients was higher compared to PTD ongoing clinical depression, so some of the changed regi- without TRD and compared to patients without PTD. This mens may have been initially effective. This may have is partly due to the fact that when a patient had a pre- affected the estimates of the durations of episodes of PTD scription renewed, that event was considered to be an and TRD and caused some PTD cases that were not TRD to outpatient visit. The finding of increased service utilization be misclassified as TRD cases. This misclassification of the TRD population holds for both the per-patient-year would result in an overestimation of the incidence of TRD. and per-patient perspective, and echoes recent findings However, this limitation is common in retrospective data- from Brazil [42] or the USA [4]. No similar difference was base studies of TRD and is difficult to avoid. Measurement seen for all types of hospital days, where PTD patients who of patient-reported outcomes or physician assessment, such were not TRD had higher resource utilization. as the antidepressant treatment response questionnaire Total treatment costs per person among TRD patients of (ATRQ) or Mini International Neuropsychiatric Interview 1.01 million JPY were higher than for patients who only (MINI) for treatment response, would not have been exhibited PTD (0.643 million JPY) or compared with the available in claims data. Future studies should validate the non-PTD population (0.327 million JPY per patient). Those findings using alternative definitions of TRD in order to are only direct medical costs that accrue to the health address the high degree of uncertainty there is surrounding insurer and a recent health economic study found that our results. Moreover, a common problem in any database analysis is the coding quality [51]. More often than not, direct medical costs constitute only 14.2% of the total cost associated with depression in Japan [43]. The biggest hospitals or physicians designate medical codes that pro- fraction of the economic burden resulted from indirect vide the highest reimbursement rates, but disease codes do costs such as productivity losses [44]. Although the mag- not always reflect clinical reality. nitude of healthcare expenditure/costs for TRD was smaller than that reported in the USA [7], this study shows the same directionality. That treatment costs are higher in the 5 Conclusions USA is a well-established result in the literature and the cited Japanese health economic study [44] found direct To the best of our knowledge, this study provides the first treatment costs to be only 50% of those in the USA [45]. population-based estimates for the incidence and related That TRD patients do incur higher costs to the healthcare costs of TRD in the Japanese population. The unmet need system has been reported for a number of other countries for better treatment of depression and the high cost of such as Brazil [42] or the USA [14, 46–48]. depression indicate a need for both society and the affected individuals for better means of prevention and treatment of 4.4 Limitations depression. Acknowledgements We want to thank Koji Shimamoto for IT sup- This study had some limitations. The study’s definition port and programming and Dan Fife for advice. could not take dosage into account when defining antide- pressant medication regimens due to substantial amounts of Compliance with Ethical Standards missing data, which is likely to affect the estimated TRD This was a retrospective database study; the authors were not incidence. However, by not using dosage as a factor, this involved in the collection of this data. Retrieval of the data from this allows more regimens to be counted and thus would cap- database occurred in an unlinked fashion. 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Treatment- resistant depression increases health costs and resource utiliza- tion. Rev Bras Psiquiatr. 2012;34(4):379–88. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Drugs - Real World Outcomes Pubmed Central

Estimating Prevalence and Healthcare Utilization for Treatment-Resistant Depression in Japan: A Retrospective Claims Database Study

Drugs - Real World Outcomes , Volume 5 (1) – Nov 28, 2017

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Drugs - Real World Outcomes (2018) 5:35–43 https://doi.org/10.1007/s40801-017-0126-5 ORIGINAL RESEARCH ARTICLE Estimating Prevalence and Healthcare Utilization for Treatment- Resistant Depression in Japan: A Retrospective Claims Database Study 1,2 1 3 • • Jo ¨ rg Mahlich Sunny Tsukazawa Frank Wiegand Published online: 28 November 2017 The Author(s) 2017. This article is an open access publication Abstract million JPY (0. 540 million JPY) in the TRD population Background Major depressive disorders (MDDs) including and 0.643 JPY million JPY (0.645 million JPY) in the PTD treatment-resistant depression (TRD) are common dis- population who did not convert into TRD. abling conditions, but data on their epidemiology in Japan Conclusions This study describes the PTD and TRD are limited. This study investigated the incidence, epi- patient populations in a large claims database in Japan and demiology, and direct medical costs of TRD and pharma- highlights an unmet medical need for the treatment of TRD ceutically-treated depression (PTD) in Japan to increase to provide better preventative measures and interventions our health economic understanding of this phenotype of for the treatment of depression. MDD. Methods A retrospective cohort study from a private health insurance claims database estimated the 1-year Key Points incidence of PTD and TRD and described the health ser- vices used and direct medical costs associated with these This is the first database study to explore prevalence conditions. and associated healthcare utilization and treatment Results In the year from 1 April 2012 through 31 March costs of treatment-resistant depression in Japan. 2013, we identified 1143 incident PTD cases among 98,552 Our findings suggest that patients suffering from eligible subjects, i.e. 11.59 cases/1000 patient-years. Of the treatment-resistant depression cause higher PTD patients, 51.4% were women. Within the 1-year healthcare costs per episode compared with patients observation interval 137 patients failed more than two with depression that is not treatment resistant. antidepressive treatment approaches and thus developed TRD. Though co-morbid conditions and age were similar among PTD and TRD patients, medical costs per patient (patient-year) during their treatment intervals were 1.01 1 Background Electronic supplementary material The online version of this It is estimated that more than 300 million people world- article (https://doi.org/10.1007/s40801-017-0126-5) contains supple- mentary material, which is available to authorized users. wide suffer from major depressive disorder (MDD) [1], and that by 2020, major forms of depression will become the & Jo¨rg Mahlich second leading cause of global disease burden after joerg.mahlich@gmail.com ischemic heart disease [2]. Depression is a current public health concern because of its early-age of onset, high Health Economics, Janssen Pharmaceutical K.K, 5-2, Nishi- kanda 3-chome, Chiyoda-ku, Tokyo 101-0065, Japan prevalence, high impact on patient quality of life and ¨ ability to function, as well as high clinical and economic Dusseldorf Institute for Competition Economics (DICE), University of Du¨sseldorf, Du¨sseldorf, Germany burden [3]. Depression can occur at any point during an individual’s lifetime and is characterized by a single or Janssen Global Services LLC, Raritan, NJ, USA 36 J. Mahlich et al. recurrent episode of clinically diagnosed depressive were estimated as 3–7 and 1–2%, respectively [21]. Inter- symptoms with variations during each episode. It is the estingly, patients with depression in Japan were reported to most common severe psychiatric illness and affects emo- be less likely to seek medical treatment or consult a psy- tions, thought, and behavior, leading to low disease-related chiatrist compared with patients in Western countries [21], quality of life. The incidence of suicide attempts is about and the lack of utilization of mental health services was not 20- to 40-fold for patients suffering from an MDD episode related to gender, age or income level. Furthermore, an [4], making suicide the second leading cause of death international WHO report indicated that in Japan the among 15- to 29-year-olds globally [5]. Japan has one of majority of people recently diagnosed with a psychiatric the highest suicide rates worldwide [6]. disorder do not seek mental healthcare or use other support Although depression can be treated pharmacologically, systems [22]. However, no longitudinal cohort studies are studies in the USA [7] and UK [8] reported that a sub- available for Japan that would allow a good estimation of stantial subset of depression patients, termed treatment- TRD rates and related costs. The aim of this study was resistant depression (TRD) patients, do not achieve an therefore to estimate the incidence, the amount of medical adequate clinical response to the administration of antide- services used, and the direct costs of PTD and TRD, pressants. The current definition of TRD lacks consensus; through a retrospective analysis of a health insurance however, the Committee for Medicinal Products for claims database and thus help improve our understanding Human Use at the European Medicines Agency defines of the socioeconomic impact of TRD in Japan. TRD as pharmacologically-treated depression (PTD) that does not show clinically meaningful improvement after at least two different antidepressant medications used for a 2 Methods sufficient length of time at an adequate dose with adequate affirmation of treatment adherence [9]. 2.1 Data Source Large longitudinal studies suggest that MDD patients who develop treatment resistance have a low chance to Health insurance claims data from non-governmental achieve response or remission with each subsequent line of employees and their family members between July 2009 treatment [10]. Although TRD patients have been charac- and March 2015 sourced from multiple health insurance terized well in regard to their clinical characteristics, associations were retrieved from the Japan Medical Data including co-morbidities, there is a paucity of data with Center (JMDC). During this period, a total of 2,958,220 regard to the epidemiological and health economic conse- patients were enrolled in the JMDC database. The database quences in Japan. Furthermore, the burden of TRD in terms provides comprehensive patient and clinical information, of disability, cost, human suffering and suicide is unclear including patient demographics, diagnostic codes, dates [11] because the accurate and systematic assessment of and types of procedures, dispensed prescription drugs, TRD, including predictive utility and reliability of TRD medical services provided to inpatients and outpatients, and staging, is difficult [12]. Usually, response is defined as a expenditures. The JMDC database has been used to reduction in depressive symptoms to\50%, and remission investigate a wide range of conditions in Japan such as as a full recovery [13]. schizophrenia [23] or cardiovascular disease [24]. All From a US economic viewpoint, patients with TRD personally identifiable information was de-identified to generate higher direct medical costs compared with those protect patient privacy. Therefore, no informed consent with MDD within a 12-month time horizon [14] and have was necessary. higher indirect productivity costs from a societal point of view [15]. One reason for this difference in economic 2.2 Selection of Study Population burden is the increased number of co-morbidities in TRD patients compared with non-TRD patients [16]. In addition, A retrospective cohort design was used. JMDC database secondary administrative data indicated that some patients members joined the study cohort on 1 April 2012 if they are treated with up to four different pharmacological were within 18–60 years of age (i.e., were born between treatments still fail to respond to treatment, and thus have 1952 and 1994), had no prior depression diagnosis (ICD higher healthcare utilization and higher per-patient medical 10; F32.x, F33.x, F34.1, F41.2, F43.2, F53.0), no previous costs [17]. diagnoses of other mental diseases (ICD 10; The estimated lifetime prevalence of MDD in the USA F0;F1;F2;F3F20; F30;F31), and no prior prescription of is 16.2% [18], and the 12-month prevalence is 6.7% [19]. any antidepressant medication before 31 March 2012. Estimations about the rate of patients developing TRD vary Antidepressant medication was defined as a medication widely from 6.6 [7] to 35% [20] of MDD patients. For that is approved for the treatment of depression in Japan. Japan, the lifetime and 12-month prevalence rates of MDD The list of antidepressant medications can be found in Prevalence and Healthcare Utilization for Treatment-Resistant Depression 37 Supplementary Table 1. Patients were censored if they threshold value allows for a better comparability across develop other psychiatric conditions as mentioned above database studies [26]. after they were included in the study cohort. As we are not able to observe symptom improvements in Based on these criteria, 98,552 patients who were con- claims databases, we acknowledge that there is some tinuous JMDC database members from 1 April 2012 through uncertainty around this definition. 31 March 2013 were included in this analysis (Table 1). Maximal follow-up time was until 31 March 2015. 2.5 Resource Utilization 2.3 Identification of a Pharmaceutically Treated Hospital claims were characterized by resource utilizations Depression (PTD) as: hospitalization in emergency department, hospitaliza- tion in psychiatric emergency department, psychiatric A pharmaceutically treated depression (PTD) treatment hospitalization, all hospitalizations, psychiatric office visit interval began when a study subject received a depression (out-patient), and office visit (out-patient). Total cost per diagnosis and simultaneously or subsequently (within less patient and total cost per patient-year were calculated. Cost than 30 days) a dispensation of an antidepressant per person-time and cost per person capture of different medication. information and the former measure adjusts for time while The start of a treatment interval was the date of the latter does not. Total cost refers to the sum of costs paid depression diagnosis or the date of antidepressant medi- by insurance and by the patients via co-insurance schemes cation dispensation, whichever was earlier. A treatment and that are paid out of pocket. The co-insurance rate is interval was terminated when the subject received no 30% for people under 70 years of age and 20% for those depression diagnosis and was dispensed no antidepressant above 70 years of age. Maximum co-payments are capped medication for 120 days. The duration of a PTD interval depending on household income ranging from 35,400 JPY was defined as the number of months from PTD index (US$307) per month for the population earning less than 1 month to the month a treatment interval ends. It is million (US$8700) a year to 252,600 JPY per month important to recall that what we call a treatment interval of (US$2200) for those with an annual income above 11.6 PTD is a sequence of dispensing of antidepressant medi- million JPY (US$100,900). Once a person turns 70 years cations and visits with a depression diagnosis, and that this old, the upper limit of the co-payments is reduced drasti- represents a treatment interval of care for PTD rather than a cally ranging from 8000 (US$70 USD) to 80,000 JPY clinical episode of clinical depression. In particular, med- (US$700) per month depending on income and whether the ication may include some prophylaxis. cost is related to in-patient or out-patient services. At the age of 75 years, everyone in Japan switches to an insurance 2.4 Identification of Treatment-Resistant scheme for the elderly that was established 2008. The Depression (TRD) common co-payment rate for this plan is 10% [27] A TRD treatment interval is a PTD treatment interval in 2.6 Statistical Analysis which two treatment regimens have failed. A treatment regimen fails when, at least 15 days after it began, an This study employed a cohort design because TRD is antidepressant medication is added or substituted for defined by a temporal sequence of events (unsuccessful another medication. We assumed 15 days as adequate treatment regimens) that may occur in a subject with PTD. threshold, because evidence suggest that nonresponse is A cohort perspective also facilitates estimation of TRD predicted by a lack of symptom improvement during the incidence and duration of treatment. This was a descriptive first 14 days of therapy [25]. Moreover, this is a common study so no effect measure was calculated. The incidence definition used in database analysis and choosing this of PTD and TRD were estimated by proportion per year. Table 1 Selection of subjects Criterion Number of patients 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 101,357 dispensing before Mar 2012 No exclusion diagnosis before Mar 2012 101,006 Database member after Apr 2012 eligible for study cohort 98,552 38 J. Mahlich et al. Group comparisons were conducted using the Kruskal– 3.2 Healthcare Utilization and Medical Costs Wallis test with post hoc Scheffe’s rank sum multiple contrast tests. All statistical analyses were performed using 3.2.1 Medication R version 3.2.1 (The R Foundation for Statistical Com- The antidepressant classes most commonly used were selec- puting, Vienna, Austria). tive serotonin reuptake inhibitors (SSRIs) followed by sul- piride instead of serotonin and noradrenaline reuptake 3 Results inhibitors (SNRIs) (Table 4). Sulpiride has been approved for the treatment of depression in Japan (150–300 mg/day dose). 3.1 Incidence and Patient Characteristics It is apparent from the table that patients received more than one antidepression medication simultaneously. For In total, 1143 (1.2%) subjects experienced 1154 PTD example, the second treatment line in the TRD population treatment intervals for the 98,552 patients contained in the consists of 264/137 = 1.92 antidepression medications per selected sample (Table 1). Of the patients who met the patient on average. inclusion criteria for PTD, 11 patients had more than one 3.2.2 Medical Service Utilization treatment interval during the study period (Table 2). If a patient had at least one TRD treatment interval, the patient In all groups, there were few psychiatric emergency hos- was classified as a TRD patient. Reasons for censoring among subjects with PTD but not TRD and among subjects pitalizations and there were none among newly developed with TRD are shown in Table 2. TRD patients. Patients with non-TRD/PTD had more One hundred and thirty-seven patients developed TRD hospitalization days per person years than TRD patients or within 1 year. TRD and non-TRD/PTD patients (i.e., subjects without PTD (3.857 vs. 1.837 vs. 1.715 days/pa- patients with PTD who did not develop TRD) were of a tient-years) (p\0.05), TRD patients had slightly more similar mean age (43.4 and 42.8 years, respectively) psychiatric hospitalization days/person years than non- (Table 3). Among patients with PTD (whether or not they TRD/PTD patients or subjects without PTD (0.895 vs. developed TRD), 556/1143 (48.6%) were male. In contrast, 0.808 vs. 0.010 days/patient-years) (p\0.0001). The number of psychiatric office visits per patient-years among those with TRD, 84/137 (61.3%) were male. TRD treatment intervals had longer durations (mean among TRD patients was much greater than for non-TRD/ PTD patients or subjects without PTD (17.370 vs. 8.528 vs. 22.0 months, median 25.0 months) than did PTD intervals without TRD (mean 11.0 months, median 7.0 months). 0.156 /patient-years) (p\0.0001). The trend was similar but much less pronounced for all office visits (TRD vs. non- TRD/PTD vs. non PTD: 45.537 vs. 37.019 vs. 21.224/pa- Table 2 Incidence of PTD and TRD tient-years) (p\0.0001). For non-PTD patients service uti- Incident PTD between Apr 2012 to Mar 2013 1143 lization is much smaller in all categories (Table 5). PTD episode censored without TRD 1006 Incident TRD 137 3.2.3 Medical Costs Incident TRD episode not censored 94 Incident TRD episode censored 43 Medical costs in millions of yen per patient were 1.014 for Reasons for censoring among subjects with PTD but not TRD those with TRD, 0.643 for those with PTD but not TRD, End of study 705 and 0.327 for the non-PTD population. Expressed in mil- Left database 230 lions of yen per patient-year, the total direct medical cost of Diagnosis of psychosis 39 TRD is 0.540 million yen, and for non-TRD/PTD it was Diagnosis of mania 5 0.645 million yen. This compares to 0.361 million yen for Diagnosis of bipolar disorder 27 the non-PTD group (Table 5)(p\0.0001). The difference Reasons for censoring among subjects with TRD between the cost per patient (which is similar to the cost End of study 94 per treatment interval) and the cost per patient-year stems Left database 27 from the different treatment durations, which are signifi- Diagnosis of psychosis 6 cantly longer in TRD patients. This reduces the cost when Diagnosis of mania 1 reported as cost per time unit. We report both measures Diagnosis of bipolar disorder 9 because for reimbursement decision makers, the cost-per- Diagnosis of dementia 0 patient approach is probably more relevant since this is the kind of cost policy makers need to deal with when it comes AD antidepressants, PTD pharmaceutically-treated depression, TRD treatment-resistant depression to budget allocation decisions. Prevalence and Healthcare Utilization for Treatment-Resistant Depression 39 Table 3 Description of study subjects and depression episodes by depression type, sex, age group, and co-morbidities Characteristic All subjects PTD subjects PTD subjects TRD PTD treatment PTD treatments TRD excl. TRD subjects intervals intervals excl. treatment TRD intervals Number 98,552 1143 1006 137 1154 1016 137 Age (years) Mean 44.7 43.4 43.4 42.8 43.3 43.4 42.8 SD 10.9 10.5 10.6 9.2 10.5 10.6 9.2 Median 46.0 45.0 45.0 44.0 45.0 45.0 44.0 n % n % n % n % n % n % n % Male age groups (years) 47,242 100% 556 100% 472 100% 84 15% 561 100% 477 100% 84 100% 18–29 4254 9.00% 51 9.20% 45 9.50% 6 1.10% 52 9.27% 46 9.64% 6 7.10% 30–39 7050 14.90% 107 19.20% 89 18.90% 18 3.20% 109 19.43% 91 19.08% 18 21.40% 40–49 14,113 29.90% 209 37.60% 171 36.20% 38 6.80% 211 37.61% 173 36.27% 38 45.20% 50–60 21,825 46.20% 189 34.00% 167 35.40% 22 4.00% 189 33.69% 167 35.01% 22 26.20% Female age groups (years) 51,310 100% 587 100% 534 100% 53 100% 593 100% 539 100% 53 100% 18–29 6364 12.40% 91 15.50% 82 15.40% 9 16.98% 92 15.51% 83 15.40% 9 17.00% 30–39 12,645 24.60% 146 24.90% 133 24.90% 13 24.53% 146 24.62% 133 24.68% 13 24.50% 40–49 14,724 28.70% 159 27.10% 140 26.20% 19 35.85% 162 27.32% 143 26.53% 19 35.80% 50–60 17,577 34.30% 191 32.50% 179 33.50% 12 22.64% 193 32.55% 180 33.40% 12 22.60% Age at onset of episode PTD pharmaceutically-treated depression, SD standard deviation, TRD treatment-resistant depression Table 4 Classes of antidepressant medications used to treat PTD and TRD Medication TRD population PTD population without TRD class 1st regimen (n = 137) 2nd regimen (n = 137) 3rd regimen (n = 137) 1st regimen (n = 1016) 2nd regimen (n = 226) (%) (%) (%) (%) (%) SSRI 80 (58.4) 94 (68.6) 94 (68.6) 424 (41.7) 124 (54.9) Sulpiride 64 (46.7) 71 (51.8) 53 (38.7) 309 (30.4) 59 (26.1) SNRI 19 (13.9) 34 (24.8) 38 (27.7) 154 (15.2) 57 (25.2) NaSSA 16 (11.7) 16 (11.7) 19 (13.9) 82 (8.1) 29 (12.8) TrCA 11 (8.0) 23 (16.8) 29 (21.2) 127 (12.5) 35 (15.5) TeCA 3 (2.2) 5 (3.6) 7 (5.1) 17 (1.7) 32 (1.3) Others 12 (8.8) 21 (15.3) 20 (14.6) 56 (5.5) 12 (5.3) Total 205 (149.6) 264 (192.7) 260 (189.8) 1169 (115.1) 319 (141.2) NaSSA noradrenergic and specific serotonergic antidepressant, PTD pharmaceutically-treated depression, SNRI serotonin and noradrenaline reuptake inhibitor, SSRI selective serotonin reuptake inhibitor, TeCA tetracyclic antidepressant, TrCA tricyclic antidepressant, TRD treatment- resistant depression Japan [28]. The estimated differences between Japan and 4 Discussion the USA or other Western countries may be partially due a greater reluctance to report depression among people in the 4.1 Incidence Japanese population than in Western countries. Compared Our study estimated the 12-month incidence of PTD as to Western countries, Japanese patients with depression were reported to have decreased behaviors of seeking any 1.2% for the privately insured population of Japan. Recent epidemiologic studies of community residents reporting the medical treatment or of consulting a psychiatrist (27% sought any; 14% consulted a psychiatrist), which is lower prevalence of major depression according to DSM-IV cri- teria was 1–2% for 12 months and 3–7% for lifetime in than that reported from many Western countries, and 40 J. Mahlich et al. Table 5 Medical services used by people during PTD episodes (with and without TRD) and by people without PTD Subjects with TRD Subjects with PTD but not TRD Subjects without PTD within first year Count (n) 137 1006 97,409 Person years (PY) 257 1003 88,154 Total Total/subject Total/PY Total Total/subject Total/PY Total Total/ Total/PY subject Hosp. days, psychiatric 230 1.679 0.895 810 0.805 0.808 878 0.009 0.010 Hosp days, all 472 3.445 1.837 3869 3.846 3.857 151,220 1.552 1.715 Psy. Emer. Dep., days 0 0.000 0.000 145 0.144 0.145 194 0.002 0.002 Emer. Dep., days 32 0.234 0.125 48 0.048 0.048 2,038 0.021 0.023 Psy. OV 4,464 32.584 17.370 8554 8.503 8.528 13,708 0.141 0.156 OV 11,703 85.423 45.537 37,130 36.909 37.019 1,870,988 19.21 21.224 Total costs 138.900 1.014 0.540 646.600 0.643 0.645 31,862.000 0.327 0.361 (million Yen) Emer. Dep. emergency department, Hosp., any hospitalization, OV any office visit, Psy. Emer. Dep emergency hospitalization to the psycho- logical department, Psy. OV office visit for psychological treatment, PTD pharmaceutically-treated depression, PY patient-year (/1,000 patient- years), TRD treatment-resistant depression Reported values are not age- or gender-adjusted approximately half of that in the USA [28]. Accordingly, 4.2 Medication previous epidemiological studies have shown a lower prevalence of depression in East-Asian countries including Prescription patterns in the study population showed that SSRIs were the most frequently used drugs, similar to the Korea, Japan, and China compared with the West [29]. Findings from the World Mental Health Japan Survey usage reported for six other East-Asian countries (at 40 2002–2003 [21] for instance suggest that the majority of sites) [32]. In contrast, a similar study in the USA reported people with a recent psychiatric disorder did not utilize that SNRIs were most frequently used [7]. mental healthcare or other support systems, despite service Another finding is the wide usage of sulpiride, which improvement over time. Such cross-cultural differences confirms results of previous studies [34]. A Japanese would equate to a higher diagnostic threshold for depres- chart review for instance found that sulpiride was the most frequently prescribed antidepressant with a share of 40.3% sion in East-Asian countries [30, 31]. Presumably, these cultural differences might also influence the gender effects in 367 outpatients with a major depressive disorder [35]. The wide use of sulpiride is somewhat unexpected given on depression. Considering Japan is in the East-Asian sociocultural realm, similar estimates after accounting for the limited evidence of its efficacy in depression. A review of the UK HTA agency NICE in 2011 identified only one sociocultural differences may be anticipated for this study. Similar to the global trend, women exhibited a greater risk clinical trial that found a statistically significant greater than men for depressive disorders in Japan, although age mean change in the 21-item Hamilton Depression Rating and social class distributions were different from other Scale with 150–300 mg sulpiride compared with placebo. countries [32]. Twelve percent of PTD patients developed NICE concluded that due to the small number of studies TRD within a year, which is in the range of estimates from and lack of study quality assessment, the effectiveness of other countries [4, 20, 33]. For Taiwan, which is culturally second-generation antipsychotics in the treatment of major depressive disorder is unclear [36]. Table 4 indicates that close to Japan, this proportion was estimated to be 21% [26]. As we utilized a database whose members include many subjects were receiving more than one medication for depression at a time, and sulpiride may have been used employees and their families, patients with a very severe history of depression might not be able to stay in to augment an antidepressant. In a Japanese clinical trial, this has been recommended as a successful strategy for employment and are therefore under-represented in this sample. This would imply a downward bias of the TRD accelerating antidepressant response [37]. incidence rate. The majority of TRD patients were male in Our results also suggest that more than one antidepres- our analysis, which is in contrast to findings from Taiwan sant medication was prescribed on average, especially in [26] or the USA [7]. Again, the composition of our data- the later treatment lines, although the link between base might be a potential explanation for this finding. polypharmacy and efficacy has not been established [38] Prevalence and Healthcare Utilization for Treatment-Resistant Depression 41 and polypharmacy is not recommended in international and requirement. Moreover, this study only investigated phar- Japanese guidelines. Instead, clinical guidelines recom- macological interventions among patients with depression. mend monotherapy with a second-generation antidepres- The role of non-pharmacological treatments, such as psy- sant for acute-phase treatment [39]. Despite this, only 26% chotherapy, was not investigated here. For that reason, the of Japanese psychiatrists treat patients with monotherapy estimates from this study are likely to be a lower bound for according to a survey by Ueshima et al. [40]. A Japanese the actual disease incidence. On the other hand, psy- claims database analysis of 7,338 Japanese patients with chotherapy is only rarely prescribed in Japan compared to depression also observed various patterns of polypharmacy its wide use in the USA [49]. Another potential limitation [41]. is that claims were used as the basis of defining events for analysis of study. In clinical practice, prophylactic mea- 4.3 Healthcare Utilization and Medical Cost sures of continued antidepressant prescriptions are taken because those that have had episodes of depression are at Some psychiatric service utilization including psychiatric increased risk for sequential episodes [45, 50]. Prophylactic hospital days, overall office visits, and psychiatric office treatment behavior would be indistinguishable from visits for TRD patients was higher compared to PTD ongoing clinical depression, so some of the changed regi- without TRD and compared to patients without PTD. This mens may have been initially effective. This may have is partly due to the fact that when a patient had a pre- affected the estimates of the durations of episodes of PTD scription renewed, that event was considered to be an and TRD and caused some PTD cases that were not TRD to outpatient visit. The finding of increased service utilization be misclassified as TRD cases. This misclassification of the TRD population holds for both the per-patient-year would result in an overestimation of the incidence of TRD. and per-patient perspective, and echoes recent findings However, this limitation is common in retrospective data- from Brazil [42] or the USA [4]. No similar difference was base studies of TRD and is difficult to avoid. Measurement seen for all types of hospital days, where PTD patients who of patient-reported outcomes or physician assessment, such were not TRD had higher resource utilization. as the antidepressant treatment response questionnaire Total treatment costs per person among TRD patients of (ATRQ) or Mini International Neuropsychiatric Interview 1.01 million JPY were higher than for patients who only (MINI) for treatment response, would not have been exhibited PTD (0.643 million JPY) or compared with the available in claims data. Future studies should validate the non-PTD population (0.327 million JPY per patient). Those findings using alternative definitions of TRD in order to are only direct medical costs that accrue to the health address the high degree of uncertainty there is surrounding insurer and a recent health economic study found that our results. Moreover, a common problem in any database analysis is the coding quality [51]. More often than not, direct medical costs constitute only 14.2% of the total cost associated with depression in Japan [43]. The biggest hospitals or physicians designate medical codes that pro- fraction of the economic burden resulted from indirect vide the highest reimbursement rates, but disease codes do costs such as productivity losses [44]. Although the mag- not always reflect clinical reality. nitude of healthcare expenditure/costs for TRD was smaller than that reported in the USA [7], this study shows the same directionality. That treatment costs are higher in the 5 Conclusions USA is a well-established result in the literature and the cited Japanese health economic study [44] found direct To the best of our knowledge, this study provides the first treatment costs to be only 50% of those in the USA [45]. population-based estimates for the incidence and related That TRD patients do incur higher costs to the healthcare costs of TRD in the Japanese population. The unmet need system has been reported for a number of other countries for better treatment of depression and the high cost of such as Brazil [42] or the USA [14, 46–48]. depression indicate a need for both society and the affected individuals for better means of prevention and treatment of 4.4 Limitations depression. Acknowledgements We want to thank Koji Shimamoto for IT sup- This study had some limitations. The study’s definition port and programming and Dan Fife for advice. could not take dosage into account when defining antide- pressant medication regimens due to substantial amounts of Compliance with Ethical Standards missing data, which is likely to affect the estimated TRD This was a retrospective database study; the authors were not incidence. However, by not using dosage as a factor, this involved in the collection of this data. Retrieval of the data from this allows more regimens to be counted and thus would cap- database occurred in an unlinked fashion. 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Published: Nov 28, 2017

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