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1 Psychiatry and Clinical Neurosciences (2007), 61, doi: /j x Regular Article International study on antidepressant prescription pattern at 20 teaching hospitals and major psychiatric institutions in East Asia: Analysis of 1898 cases from China, Japan, Korea, Singapore and Taiwan NAOKI UCHIDA, md, 1 MIAN-YOON CHONG, md, phd, 2 CHAY HOON TAN, md, phd, 3 HIROSHI NAGAI, md, phd, 1 MARIKO TANAKA, md, 1 MIN-SOO LEE, md, phd, 4 SENTA FUJII, md, 5 SHU-YU YANG, msc, 6 TAINMEI SI, md, 7 KANG SIM, md, 2 HAO WEI, md, phd, 8 HE YAN LING, md, phd, 9 RYOJI NISHIMURA, md, phd, 1 YOSHICHIKA KAWAGUCHI, phd, 10 GLEN EDWARDS, phd, 11 NORMAN SARTORIUS, md, phd 12 AND NAOTAKA SHINFUKU, md, phd 13 1 Fukuoka University College of Medicine, 10 Kyusyu University College of Medicine, 13 Seinan-Gakuin University, Fukuoka, 5 Hyogo Mental Health Center, 11 Kobe University School of Medicine, Kobe, Japan, 2 Chang Guan Memorial Hospital, 6 Kaohsiung Medical University, Kaohsiung, Taiwan, 3 National University of Singapore, Singapore, 4 Korea University College of Medicine, Seoul, Korea, 7 Beijing Institute of Mental Health, Beijing, 8 Central South University, Changsha, 9 Shanghai Institute of Mental Health, Shanghai, China and 12 University of Geneva, Geneva, Switzerland Abstract The purpose of the present study was to review the prescription patterns of antidepressants in different countries in East Asia. The survey was conducted in China, Japan, Korea, Singapore and Taiwan from October 2003 to March 2004 using the unified research protocol and questionnaire. Twenty teaching hospitals and major psychiatric hospitals participated and a total of 1898 patients receiving antidepressants were analyzed. The survey provided a number of interesting characteristics on the prescription patterns of antidepressant in East Asia. Out of 56 antidepressants listed in the Anatomical Therapeutic Chemical Classification (ATC) index by the World Health Organization (WHO) Collaborating Center for Drug Statistics Methodology (Oslo), only 26 antidepressants were prescribed in participating countries in East Asia. On average 38.4% of prescriptions of antidepressants were for patients with diagnoses other than depressive disorders. The availability and commonly prescribed antidepressants varied greatly by country. The selective serotonin re-uptake inhibitors (SSRI) and other newer antidepressants were prescribed in approximately 77.0% of all cases. At the time of the survey, only two SSRI medications were available in Japan. However, five types of SSRI were available and were often prescribed in Korea. Key words antidepressant, East Asia, international collaboration, prescription patterns, SSRI. INTRODUCTION Since the introduction of selective serotonin re-uptake inhibitors (SSRI) in 1988 many countries have Correspondence address: Naoki Uchida, MD, Faculty of Psychiatry, School of Medicine, Fukuoka University, Nanakuma, Jyoto-ku, Fukuoka , Japan. naoki.uchida. fukuoka@jcom.home.ne.jp Received 28 December 2006; revised 4 April 2007; accepted 29 April reported a marked increase in the use of antidepressants, 1,2 with their use doubling from 1985 to This trend is continuing as each year new antidepressants enter the market place. With the increase of new antidepressants, psychiatrists now have ample choices for their preferred use of such medications. Clinical practice guidelines for depression include many types of antidepressants for prescription by psychiatrists and general physicians. 4 New types of antidepressants are used for a variety of conditions because they are

2 Antidepressant use in East Asia 523 reported as having fewer side-effects. 5,6 Increased use of antidepressants was reported in Canada from 1981 to Several studies listed avoidance of specific side-effects as the most common factor influencing antidepressant selection. A recent study supports a policy of recommending SSRI as the first choice of antidepressants in primary health care. 8 Treatment of patients who suffer from depression is now a priority in the clinical work of psychiatry in East Asia. However, compared to the vast literature on the use of antidepressants in USA and in Europe, there is a scarcity of data on their use in East Asia. 9,10 Our research group undertook a collaborative study on the prescription pattern of antipsychotics in East Asia using the unified research protocol and found marked differences in the use of antipsychotics among countries in East Asia. 11,12 Polypharmacy and the prescription of high-dose antipsychotics in Japan were highlighted in a previous study. 11 For our collaborative research on the prescription pattern of antidepressants, we hypothesized that there would be a marked increase in the use of SSRI and differences in the prescription of antidepressants among countries in East Asia. The purpose of the present study was manifold. First, it was designed to collect clinical data highlighting the prescription patterns of antidepressants in East Asia. In the past, there have been limited studies showing the actual prescription patterns of antidepressants in East Asia. Second, it was considered important to review the trend of the prescription for the so-called newer antidepressants that emerged into Asian markets during the late 1990s. Currently, prescription patterns are changing very rapidly due to the introduction of new drugs. It was deemed timely to undertake a survey and to follow up the emerging trends. Third, it was felt necessary to identify the rate of prescriptions of antidepressants for different diagnostic criteria. There is widespread awareness of antidepressants being prescribed to patients with diagnoses other than F3 depressive disorders. 3,13 However, the extent of this practice is not clear. Findings of this research could be used in promoting the appropriate use of antidepressants by primary care physicians. METHODS Unified research protocol and questionnaire Researchers from five countries in East Asia China, Japan, Korea, Singapore and Taiwan prepared a unified research protocol and questionnaire. The research protocol was reviewed and approved by the Research Committees at National University of Singapore and Fukuoka University Medical College, which played the leading roles in the design of the research protocol. The Research and Ethics Committees of the coordinating university in each country approved the study. Each participating institution approved the survey protocol. Researchers at 21 hospitals in the five countries were psychiatrists and they reviewed the patient files. They obtained approval from directors to participate in the research. At the time of the beginning of the research in 2003, very few hospitals had research committees. Many hospitals in China, Korea and Taiwan did not consider that this research required the approval from the research committee. Two consensus meetings were held in 2002 and 2002 before the study to discuss methodological issues such as data collection and uniform data entry. Randomized trials were conducted using the identical data form at 21 hospitals in five countries. Participating centers The research network began in 1999 as an international collaborative research project among universities in East Asia (supported by Japan Society for Promotion of Science). Therefore, the initial participating centers were primarily psychiatric departments and psychiatric hospitals attached to leading universities in China, Japan, Korea, Singapore and Taiwan. Coordinators of each country led the research team that reviewed the medical records of patients. In all cases, psychiatrists responsible for the patients completed the form. A total of 21 medical institutions participated in the survey. Eleven were public hospitals and 10 were private hospitals. The study included 506 cases from six psychiatric hospitals, 280 cases from psychiatric departments of two general hospitals and 1112 cases from 12 university hospitals. Data were collected on both inpatients and outpatients. Some 2952 cases were collected from the 21 participating hospitals during the field survey period of 6 months from October 2003 to March A total of 1054 entries collected from Singapore National Hospital using the computer were not included for analysis because data were not complete. In all, the survey compiled and analyzed 1898 valid entries from 20 psychiatric institutions. Data form The data form was evaluated and agreed upon by participating centers. Background information collected

3 524 N. Uchida et al. Table antidepressants in the ATC index No. Generic name No. Generic name No. Generic name No. Generic name 101 Alaproclate 116 Fluvoxamine 131 Moclobemide 146 Tianeptine 102 Amineptine 117 Imipramine 132 Nefazodone 147 Toloxatone 103 Amitriptyline 118 Imipramine oxide 133 Nialamide 148 Tranylcypromine 104 Amoxapine 119 Iprindole 134 Nomifensine 149 Trazodone 105 Bifemelane 120 Iproclozide 135 Nortriptyline 150 Trimipramine 106 Butriptyline 121 Iproniazide 136 Opipranmol 151 Tryptophan 107 Citalopram 122 Isocarboxazide 137 Oxaflozane 152 Venlafaxine 108 Clomipramine 123 Lofepramine 138 Oxitriptan 153 Viloxazine 109 Desipramine 124 Maprotiline 139 Paroxetine 154 Zimeldine 110 Dibenzepin 125 Medifoxamine 140 Phenelzine 155 Escitalopram 111 Dimetacrine 126 Melitracen 141 Pivagabine 156 Gepirone 112 Dosulepin 127 Mianserin 142 Protriptyline 113 Doxepine 128 Milnacipran 143 Quinupramine 114 Etoperidone 129 Minaprine 144 Reboxetine 115 Fluoxetine 130 Mirtazapine 145 Sertraline ATC, Anatomical Therapeutic Chemical Classification. from the case records included age, gender, ICD-10 diagnosis, treatment setting (inpatient vs outpatient, public vs private hospitals, psychiatric hospitals vs psychiatric departments in general hospitals) as well as name and dose of psychotropic medications prescribed by the psychiatrist. One merit of this study was that the psychiatrist responsible for the treatment of the patients completed the form. Inclusion criteria The inclusion criterion was receiving antidepressant medications on the day of the survey. There were several interpretations of what constituted antidepressants. For the survey, the term antidepressants was agreed to mean 56 antidepressants classified as antidepressants in the Anatomical Therapeutic Chemical Classification Index with Defined Daily Doses 2003 (ATC-DDD) by the World Health Organization (WHO) Collaborating Center for Drug Statistics Methodology. 14 Therefore, only 56 listed agents were included. ATC-DDD is reviewed and published annually by the WHO Collaborating Center for Drug Statistics Methodology (Oslo). Table 1 lists the 56 antidepressants in the ATC index. There is some criticism of the ATC list because other drugs are frequently prescribed as an antidepressant in certain countries. For example, sulpiride is one of the most frequently prescribed psychotropic drugs for depressive patients in Japan. 15,16 However, sulpiride is listed as an antipsychotic not an antidepressant in the ATC list. The research team strictly followed the ATC list as one of the entry criteria. In the survey, adjunctive psychotropic medications that were prescribed were also recorded. Data collection and analysis Psychiatrists at participating institutions in different localities screened all patients prescribed antidepressants and filled out the forms during October 2003 and March Uniform data entry format was adhered to in all cases. Coordinators at participating centers collected data and then sent it to the national coordinating centers of each country (Kaohsiung, Kobe, Seoul, Shanghai and Singapore). Each national coordinating center compiled data and forwarded it to the overall coordinator in Kobe, Japan for compilation and analysis. A small number of data entries were excluded due to incomplete data such as gender and age. As mentioned previously, data entered using a computer at the National Singapore General Hospital was not included in the analysis. Only questionnaires completed by psychiatrists were included for final compilation and analysis. RESULTS Demography and diagnosis Table 2 presents demographic data and diagnosis of entered cases. The number of entries differs by country. At first, each country was asked to collect data for at least 100 cases. However, the number varied depending upon the available time and resources utilized by psychiatrists to complete the form. With regard to gender,

4 Antidepressant use in East Asia 525 Table 2. Patients treated with antidepressants China (n = 537) Japan (n = 609) Korea (n = 293) Singapore (n = 72) Taiwan (n = 387) Total (n = 1898) Age (years) Mean SD Gender Male (%) Female (%) Treatment settings (1) Outpatient or inpatient Outpatient (%) Inpatient (%) (2) Public or private hospital Public hospital (%) Private hospital (%) (3) Psychiatric or general hospital Psychiatric hospital (%) General hospital (%) Diagnosis ICD-10 F3 (%) ICD-10 F4 (%) ICD-10 F2 (%) Others (%) Newer antidepressants (%) % (776 patients) were male, and 59.1% (1122 patients) were female. The tendency to more female (59.1%) than male patients (40.9%) was common for all countries involved. Of 1898 patients receiving antidepressant medications, 61.6% (1170) were diagnosed as having F3 mood disorder. Antidepressants were prescribed for other diagnoses such as F4 neurosis and F2 schizophrenia. Antidepressants drugs prescribed in the survey According to ATC-DDD 56 drugs are listed under the category of antidepressant. The survey showed that only 26 of 56 antidepressants were prescribed in countries in East Asia that participated in the survey. It is unlikely that other antidepressants actually prescribed are missing from the list given the large sample size. Choices of antidepressants in East Asia According to the analysis of all 1898 entries, paroxetine was the most frequently prescribed antidepressant, followed by fluoxetine, trazodone, fluvoxamine, sertraline, citalopram, milnacipran, venlafaxine, amitriptyline and mirtazapine at the time of the survey (October 2003 March 2004). Table 3 shows the list of antidepressants frequently prescribed in participating countries. However, this list may be changing rapidly due to the entrance of new drugs into the market. Newer antidepressants It is noteworthy that at the time of the survey (October 2003 March 2004), SSRI and other newer antidepressants were prescribed for approximately 77.0% of all patients. Trazodone, nefazodone, milnacipran, venlafaxine and mirtazapine were prescribed as other newer antidepressants in countries surveyed. Among newer antidepressants, SSRI accounted for 50.4%. A total of 26.6% was for other newer antidepressants. These rates are similar to those in other countries. 3,7,9 However, the order differs greatly by country. DISCUSSION The present study is not an epidemiological survey in a strict sense. This is instead a collection of raw data regarding the prescription of antidepressants of several countries in East Asia.

5 526 N. Uchida et al. Table 3. Ranking of antidepressants prescribed (n = 1898) Antidepressant n (%) 1 Paroxetine 426 (22.4) 2 Fluoxetine 264 (13.8) 3 Trazodone 226 (11.9) 4 Fluvoxamine 159 (8.4) 5 Sertraline 128 (6.7) 6 Citalopram 125 (6.6) 7 Milnacipran 124 (6.5) 8 Venlafaxine 119 (6.3) 8 Amitriptyline 119 (6.3) 8 Mirtazapine 112 (5.9) 11 Clomipramine 89 (4.7) 12 Maprotiline 78 (4.1) 13 Mianserin 53 (2.8) 14 Imipramine 48 (2.6) 15 Amoxapine 30 (1.6) 16 Nortriptyline 21 (1.1) 17 Tianeptine 16 (0.8) 18 Doxepine 13 (0.7) 19 Dosulepin 10 (0.5) 19 Melitracen 10 (0.5) 21 Moclobemide 6 (0.3) 22 Amineptine 3 (0.2) 22 Lofepramine 3 (0.2) 22 Escitalopram 3 (0.2) 25 Gepirone 2 (0.1) 26 Nefazodone 1 (0.1) Underline, selective serotonin re-uptake inhibitor and serotonin noradrenalin reuptake inhibitor. Prescription patterns of antidepressants depended greatly on the environments where the prescriptions were collected. In China five psychiatric institutions participated and data for 537 patients were collected. In total, 17 different types of antidepressants were prescribed. Mood disorder (F3) accounted for 56.2% followed by F4 (22.7%). The F4 category included generalized anxiety disorder, obsessive compulsive disorder, panic disorder and hypochondria. Antidepressants were widely used in clinical practice for anxiety disorders as an anxiolitic. These two categories, together with F2 category disorders (12.3%), mainly schizophrenia with depressive symptoms or schizoaffective disorders, accounted for 91.2% of the patients prescribed antidepressants. Most samples were collected at psychiatric hospitals and general hospitals affiliated with leading universities in Beijing, Shanghai and Changsha. More outpatients (51.6%) were included in this sample but with little difference between the two groups. Fluoxetine was the most prescribed antidepressant (33.0%) followed by paroxetine. The three most prescribed antidepressants were SSRI. However, this cannot be generalized because most of the samples were collected in large cities where social and economic conditions are different to those in rural areas. In Japan seven hospitals participated and data on 609 patients were collected. Participating centers included both private and public hospitals. Also, the samples were both from inpatient and outpatient groups. Japan had several interesting characteristics regarding the prescription of antidepressants. Only two SSRI were available at the time of the survey. This resulted in the small number of selection of antidepressants. Out of the 10 most frequently prescribed antidepressants for the total sample, only five antidepressants were available. Also, the frequent prescription of sulpiride as an antidepressant was reported. As for diagnoses, 63.4% of patients were reported as having F3 mood disorder. In Korea, four hospitals participated and data for a total of 293 patients were collected. Most cases in Korea were from the Depression Research Center of Korea University College of Medicine. The center is well known as the leading center treating depression and attracting many patients suffering from depression. Therefore, patients with F3 mood disorder diagnoses contributed to a considerably higher rate. Five types of SSRI were available and were often prescribed. The most frequently prescribed antidepressant was citalopram (23.9%). However, these results could be associated with sampling bias therefore they may not represent the average situation in Korea. In Singapore data on 72 patients from the Institute of Mental Health (only state psychiatric hospital in Singapore) were included. Consequently, many of the samples were for schizophrenia patients receiving antidepressants. Among the samples surveyed, patients with the diagnoses of depression represented only 27.8%. Patients with the diagnoses of schizophrenia represented 48.6%. Fluvoxamine and fluoxetine were most commonly used. The number of valid samples was small and samples were limited to outpatients from the one large psychiatric hospital. Separately, a large number of data were collected from a general hospital setting using the computer-assisted screening program. Antidepressants were prescribed at various departments such as obstetrics and gynecology, pediatrics and the terminal care unit. However, the data were not complete and therefore were not considered appropriate to be included in the data analysis. In Taiwan three hospitals near Kaohsiung participated, with data on 387 patients collected. A considerable number of samples were from psychiatric hospitals. This explains a relative low rate (58.7%) of patients with depression. One interesting characteristic

6 Antidepressant use in East Asia 527 of the prescription of antidepressants in Taiwan was the frequent use of trazodone. A noticeable characteristic in the present study was the use of antidepressants for a variety of psychiatric diseases. This survey confirmed that antidepressants were prescribed not only to depressed patients but also to patients with other diagnoses. The aforementioned tendency was common to all participating countries in East Asia. The rate of prescription antidepressants to other categories other than F3 differs depending on the nature of samples. It is generally believed that approximately one-third of the total entries (1898) belong to diagnostic categories other than depressive disorders. Especially, in Singapore and Taiwan, F2 patients likely received antidepressants. This tendency was common in the Research on East Asia Prescription Pattern antipsychotic study. 11,12 It should be noted that all participating centers were psychiatric institutions and all researchers were psychiatrists. Experienced psychiatrists made the diagnoses in all 1898 cases. A glimpse from the survey from different departments at Singapore General Hospital suggests that antidepressants were widely prescribed in several medical disciplines other than psychiatry. Since the introduction of SSRI in 1988, many countries have reported a marked increase in the use of antidepressants. 1,2 In the present study, SSRI and other newer antidepressants were identified as being prescribed in the treatment regimens for approximately 77.0% of patients. There was a high rate of variation in each country. The variation appeared to be influenced by difference in availability and economical settings. 17 Market forces are considered to play an important role in the choice of preferred antidepressants in participating countries. 18 It is difficult to determine from a scientific base why a particular antidepressant becomes the number one choice in certain countries. 19 It was found that government policy for licensing of drugs plays a decisive role in the availability of antidepressants. For example, only two SSRI were available in Japan at the time of the survey. In clinical settings the cost of an individual antidepressant per gross national product in each country may be an important factor for a doctor choosing to prescribe a particular antidepressant. 20 In addition, prescription choice is influenced by the coverage of the insurance scheme for a particular antidepressant. 17 The present study shows that single antidepressant prescription was common for antidepressants. In total, monopharmacy occurred in 85.9% of cases (1631 patients). There are certain differences in the rate of monopharmacy across countries. In Singapore 96.6% of patients received only one antidepressant. In contrast, in Korea 75.1% of all patients received one antidepressant. Two antidepressants were prescribed in 13.1% of all cases (antidepressant two-combination therapy). Three antidepressants were prescribed for 1.0% of patients. In an extreme situation, four antidepressants were prescribed for one patient in Japan. Study limitations The authors are aware of several limitations. The first limitation is related to the sampling bias. The data were collected from five different countries through personal networking. This inevitably invites sampling bias because many of the research team members work at university hospitals in major cities. The second limitation is related to the analysis of data. The number entered from each country differs greatly depending upon the different local conditions of the participating country. When the data were pooled for analysis, the outcome may have been influenced by the amount of data. Third, there was a limitation to achieve a common agreement on certain issues. We were faced with several different views of many contributors during the planning. During discussions, the question was raised about the different definition of old and new antidepressants in participating countries. Also, dose and cost were not fully analyzed in the present study. Differences in health policy, per capita income and medical tradition of participating countries were too great to undertake a comprehensive analysis of such data. These subjects will be left for further analysis and discussion. In spite of the limitations mentioned, the results of the study will make an important contribution in East Asia. The results of this research are expected to have an impact on the education of psychopharmacology in East Asia. Also, the data show that primary health physicians should be given additional information and training to increase the awareness of prescription patterns for antidepressants. Psychiatrists are busy with patients and are not always aware of prescription patterns of other countries. The understanding of prescription patterns in other countries will surely contribute to the improved prescription, self-evaluation and control of antidepressants. ACKNOWLEDGMENT Japan Society for Promotion of Science (JSPS) supported the research. REFERENCES 1. Ciuna A, Andretta M, Corbari L et al. Are we going to increase the use of antidepressants up to that of benzodiazepines? Eur. J. Clin. Pharmacol. 2004; 60:

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