Adjunctive antidepressant prescriptions for hospitalized patients with schizophrenia in Asia ( )

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1 bs_bs_banner Offi cial journal of the Pacifi c Rim College of Psychiatrists Asia-Pacific Psychiatry ISSN ORIGINAL ARTICLE Adjunctive antidepressant prescriptions for hospitalized patients with schizophrenia in Asia ( ) Yu-Tao Xiang 1,2 MD PhD, Gabor S. Ungvari 3 MD PhD, Chuan-Yue Wang 2 MD PhD, Tian-Mei Si 4 MD PhD, Edwin H.M. Lee 5 MD, Helen F.K. Chiu 1 MD, Kelly Y.C. Lai 1 MD, Yan-Ling He 6 MD, Shu-Yu Yang 7 PhD, Mian-Yoon Chong 8 MD PhD, Chay-Hoon Tan 9 MD, Ee-Heok Kua 10 MD, Senta Fujii 11 MD PhD, Kang Sim 12 MD, Michael K.H. Yong 13 MD, Jitendra K. Trivedi 14 MD, Eun-Kee Chung 15 MD PhD, Pichet Udomratn 16 MD, Kok-Yoon Chee 17 MD, Norman Sartorius 18 MD PhD & Naotaka Shinfuku 19 MD PhD 1 Department of Psychiatry, Chinese University of Hong Kong, Hong Kong, China 2 Mood Disorders Center, Beijing Anding Hospital, Capital Medical University, Beijing, China 3 School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia 4 Key Laboratory of Mental Health, Ministry of Mental Health and Peking University Institute of Mental Health, Beijing, China 5 Department of Psychiatry, University of Hong Kong, Hong Kong, China 6 Department of Psychiatric Epidemiology, Shanghai Mental Health Center, Shanghai, China 7 Department of Pharmacy, Taipei City Hospital, Taipei, Taiwan 8 Kaohsiung Chang Gung Memorial Hospital and Chang Gung University School of Medicine, Kaohsiung, Taiwan 9 Department of Pharmacology, National University of Singapore, Singapore 10 Department of Psychological Medicine, National University of Singapore, Singapore 11 Hyogo Institute for Traumatic Stress (HITS), Kobe, Japan 12 Department of General Psychiatry, Institute of Mental Health, Buangkok View, Singapore 13 Department of Medicine, Alexandra Hospital/Jurong Health Services, Singapore 14 Department of Psychiatry, C.S.M. Medical University UP, Lucknow, Uttar Pradesh, India 15 Department of Psychiatry, National Seoul Hospital, Seoul, Korea 16 Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand 17 Department of Psychiatry and Mental Health, Tunku Abdul Rahman Institute of Neuroscience, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia 18 Association for the Improvement of Mental Health Programs, Geneva, Switzerland 19 Department of Social Welfare, School of Human Sciences, Seinan Gakuin University, Fukuoka, Japan Keywords antidepressant, prescription pattern, schizophrenia Correspondence Yu-Tao Xiang MD PhD, Department of Psychiatry, Chinese University of Hong Kong, Ground Floor, Multicentre, Tai Po Hospital, Tai Po, N.T., Hong Kong, China. Tel: Fax: xyutly@gmail.com Received 12 April 2012 Accepted 18 July 2012 DOI: /j x Abstract Introduction: Little is known about the prescription patterns of adjunctive in Asian schizophrenia patients. This study aimed to examine trends in the use of and their demographic and clinical correlates in the treatment of schizophrenia in Asia between 2001 and Methods: A total of 6,761 hospitalized schizophrenia patients in nine Asian countries and territories were examined: 2,399 in 2001, 2,136 in 2004 and 2,226 in Patients socio-demographic and clinical characteristics and prescriptions of psychotropic drugs were recorded using a standardized protocol and data collection procedure. Results: The proportion of antidepressant prescription was 6.8% in the whole sample; 5.3% in 2001, 6.5% in 2004 and 8.7% in There were wide inter-country variations at each survey ranging from 0.9% in Hong Kong to 15.3% in Singapore in 2001; from 1.9% in Korea to 15.4% in Singapore in 2004; and from 2.7% in Japan to 22.0% in Singapore in Multiple logistic regression analysis of the whole sample revealed that patients on were younger, more likely to receive benzodiazepines and have significant extrapyramidal side-effects and less likely to have significant positive symptoms. Discussion: Unlike findings in Western countries, adjunctive antidepressant prescription for schizophrenia was not common in Asia. The frequency of antidepressant prescription varied among countries and territories, suggesting that a host of clinical and socio-cultural factors played a role in determining antidepressant use in Asia. E81

2 Antidepressants for schizophrenia Y.-T. Xiang et al. Introduction Depressive symptoms are common at all stages of schizophrenia, leading to potentially serious consequences. For example, approximately 5 10% of schizophrenia patients will eventually commit suicide (Miles, 1977; Palmer et al., 2005); more than half of them with a history of a depressive episode (Roy, 1986). Effective treatment of comorbid depression in schizophrenia could reduce suicide risk and improve quality of life (Whitehead et al., 2003). As the mainstay of treatment for depressive episodes, have been commonly prescribed in schizophrenia; approximately one-third of schizophrenia patients in Western settings receive, although the rationale for this prescription is still controversial (Chakos et al., 2006; Himelhoch et al., 2012). To date, however, most previous findings were obtained in Western settings and little is known about the prescription patterns of in Asian schizophrenia patients. In 1999 a large-scale longitudinal, observational, pharmaco-epidemiological project was launched in six Asian countries and territories (China, Hong Kong, Japan, Korea, Singapore and Taiwan) entitled the Research on Asian Psychotropic Prescription Pattern (REAP) study. REAP was initiated to investigate the prescription trends for psychotropic drugs in schizophrenia inpatients in Asia. The second REAP survey in 2004 found that 6.5% of schizophrenia inpatients in Asia were prescribed (Sim et al., 2010). To examine the trend in prescription patterns for schizophrenia and further clarify the use of psychotropic drugs in this patient population over the past decade, a third survey was conducted in 2009 using the same research design. This study aimed to (i) examine the patterns of antidepressant prescriptions for hospitalized schizophrenia patients in Asia and the prescription trends from 2001 to 2009; and (ii) to explore the demographic and clinical correlates of adjunctive antidepressant treatment. Methods Settings, study design and subjects The first REAP survey was carried out in July 2001 followed by the second and third surveys in July 2004 and October 2008 to March 2009, respectively, using the same design and standardized protocol. In the third round of the survey, participating institutions started data collection at different times; therefore, the survey lasted six months in total but data collection in each site was completed within one month, consistent with the 2001 and 2004 surveys. India, Malaysia and Thailand joined the REAP project in Consensus meetings to discuss data collection and entry were held before each survey. Participating patients had to meet the following study criteria: (i) diagnosis of ICD-10 or DSM-IV schizophrenia; and (ii) ability to comprehend the aims of the study. Patients with clinically significant medical illnesses were excluded. Doses of antipsychotics were converted into chlorpromazine equivalent milligrams (CPZeq) (APA, 1997; Kane et al., 1998; Woods, 2003). The study was approved by the clinical research ethics committees of the respective centers. Given the anonymous nature of this observational study and the minimal risk to patients, informed consent was not required at some study sites provided that only the case notes were reviewed in line with local ethical standards (Shinfuku and Tan, 2008). All patients who were interviewed gave written or verbal consent according to the requirements of the respective clinical research ethics committees, which varied across different study sites. Eligible patients were enrolled consecutively at each site. Socio-demographic and clinical characteristics including age, sex, type of psychotropic drugs prescribed, including antipsychotics, and benzodiazepines, significant positive and negative symptoms in the past month, and extrapyramidal side-effects (EPS) were collected using a questionnaire designed for the study. The above data were collected by a review of medical records in 2001 and by either a review of medical records only or a review supplemented by a clinical interview in 2004 and Data were collected by the patients attending psychiatrists or by members of the research team with the agreement of the psychiatrist in charge of the patient. Statistical analysis The data were analyzed using SPSS 13.0 for Windows (SPSS Inc., Chicago, IL, USA). Comparisons among the three surveys with respect to the proportion of patients prescribed in each study site were conducted using chi-square tests. Multiple logistic regression analysis with the Enter method (where all the independent variables were entered in the model at the same time) was used to determine the demographic and clinical variables independently influencing. The level of significance was set at 0.05 (two-tailed). E82

3 Y.-T. Xiang et al. Antidepressants for schizophrenia Results Altogether, 31 psychiatric facilities participated in 2001, 25 in 2004 and 50 in A total of 6,761 patients were involved: 2,399, 2,136, and 2,226 patients in 2001, 2004 and 2009, respectively. Table 1 shows the demographic and clinical characteristics and use of psychotropic drugs of the whole sample and separately for patients by study site and time of the survey. In the whole sample, there was a significant increase in the frequency of antidepressant prescriptions from 2001 to 2009 (c 2 = 20.7, d.f. = 2, P < 0.001). This increase was significant in Korea (c 2 = 32.9, d.f. = 2, P < 0.001) and Taiwan (c 2 = 8.2, d.f. = 2, P = 0.02). In contrast, there was no change in China (c 2 = 4.9, d.f. = 2, P = 0.08), Japan (c 2 = 0.4, d.f. = 2, P = 0.8) and Singapore (c 2 = 2.5, d.f. = 2, P = 0.3). Hong Kong had a significant change among the three surveys (c 2 = 12.9, d.f. = 2, P = 0.002), with an increase in 2004, and then a decrease in Figure 1 depicts the use of in participating countries and regions over the study period. Table 2 presents the list of frequently prescribed ; trazodone and fluoxetine were the most common followed by fluvoxamine, sertraline and paroxetine. Table 3 displays the independent factors that were significantly associated with antidepressant use. Patients on were younger and more likely to receive benzodiazepines and had less severe positive symptoms and more EPS. Discussion In contrast to earlier findings that adjunctive psychotropic medications, such as mood stabilizers and benzodiazepines, were commonly prescribed in Asian inpatients with schizophrenia (Xiang et al., 2007, 2012; Sim et al., 2011), in the present study only a small proportion of Asian schizophrenia inpatients (6.8% in the pooled sample) received antidepressant treatment from 2001 to 2009, although the frequency increased over time, from 5.3% in 2001 to 6.5% in 2004, and to 8.7% in This small increase might possibly be explained by the introduction and widespread use of newer and the increasing impact of pharmaceutical companies over the past decade. The frequency of antidepressant prescriptions in the current sample is considerably lower than has been reported for Western patients. For example, in the Clinical Trials of Intervention Effectiveness (CATIE) study in the USA 38% of patients received at least one antidepressant at baseline (Chakos et al., 2006). In another study Himelhoch et al. (2012) analyzed the data from the Veteran Administration s Mid- Atlantic region in the USA and found that 37.4% of outpatient veterans with schizophrenia received an antidepressant prescription. Similarly, Acquaviva et al. (2005) surveyed 5,257 prescriptions for 922 French schizophrenia outpatients, and found that were prescribed for 31.2% in their sample. Usually, hospitalized patients are expected to receive higher rates of adjunctive psychotropic medications relative to outpatients because they often present with more severe illness. Surprisingly, although only hospitalized patients were included in REAP surveys, the frequency of antidepressant prescription in this study was still much lower than the figures in the West. One possible reason for the low rate of antidepressant prescriptions in Asian patients compared to their Western counterparts may be the lack of compelling evidence for the usefulness of antidepressant prescription in schizophrenia (Himelhoch et al., 2012). Western treatment guidelines, such as the Schizophrenia Patients Outcome Research Team (PORT) (Lehman et al., 2004), recommended that be used to treat comorbid depression in schizophrenia, which may have promoted antidepressant prescription in Western, but not in Asian settings. We assume that perhaps Asian psychiatrists are more evidence-based than their Western counterparts, thus less were prescribed in the past decade. Another possible reason may be the different awareness and detection of comorbid depression in schizophrenia between Asian and Western settings. Another intriguing finding is the considerable variation in antidepressant prescription within Asia. The prevalence of antidepressant use varied from 0.9% in Hong Kong to 15.3% in Singapore in 2001; from 1.9% in Korea to 15.4% in Singapore in 2004; and from 2.7% in Japan to 22.0% in Singapore in The prescription pattern of in Hong Kong was unusual; an increase by 2004 followed by a decrease in 2009; this could be partly explained by the fact that in Hong Kong all subjects in the 2001 and 2004 surveys were recruited in a rehabilitation unit, whereas those in 2009 were from an acute psychiatric hospital. A number of biological, socio-cultural and economic factors, including psychopharmacological traditions, access to psychotropic drugs, cost, insurance coverage, and health care policy might all contribute to the variability across countries in antidepressant prescribing. For example, fluoxetine was not available in Japan until recently; fluoxetine 20 mg in Singapore costs $US 0.19 and in China $US E83

4 Antidepressants for schizophrenia Y.-T. Xiang et al. Table 1. Socio-demographic and clinical characteristics and psychotropic drug prescription in Asia in 2001, 2004 and 2009 China Hong Kong Japan Korea Singapore Taiwan India Thailand Malaysia Total Patients (n) Age (years) Mean SD CPZeq (mg/d) Mean SD Length of illness (>5 years; %) Men (%) Presence of positive symptoms (%) Presence of negative symptoms (%) EPS (%) FGA (%) SGA (%) APP (%) Antidepressants (%) Centers in India, Malaysia, and Thailand joined the survey in APP, antipsychotic polypharmacy (more than one antipsychotic medication); CPZeq, chlorpromazine equivalents; EPS, extrapyramidal symptoms; FGA, first-generation antipsychotic; SGA, second-generation antipsychotic. E84

5 Y.-T. Xiang et al. Antidepressants for schizophrenia * Centers in India, Malaysia, and Thailand joined the survey in 2009 Figure 1 Percentage of Asian schizophrenia patients receiving (n = 6,761). Centers in India, Malaysia, and Thailand joined the survey in : 2001; : 2004; : Antidepressant prescription was associated with a host of demographic and clinical variables. The association between increased antidepressant prescription and younger age might be explained by the belief that risk of adverse drug effects of psychotropic drugs increases with age. As a result, younger patients are more likely to receive adjunctive than older patients. Antidepressants are assumed to have activating properties (Benca et al., 1997); therefore, they are usually prescribed to treat depressive or negative symptoms (Deutsche Gesellschaft für Psychiatrie, Psychotherapie und Nervenheilkunde [DGPPN], 1998)). We assume that in order to avoid worsening positive symptoms, are less prescribed in Asian patients with severe positive symptoms. In addition, some manifestations of EPS, such as dysphoria and pseudo-parkinsonism, may appear similar to depressive symptoms, which may account for the association between presence of EPS and increased use of. Although not assessed in this study, comorbid anxiety often co-occurs with depressive symptoms in schizophrenia (Huppert et al., 2001), which perhaps accounts for the positive association between antidepressant and benzodiazepine prescriptions observed in this study. There are several limitations to this study. First, as the study sample comprised only hospitalized patients in nine Asian countries and territories, the results are necessarily restricted to this segment of the schizophrenia population in this part of Asia. Second, a number of variables, such as prior psychotropic prescriptions, treatment response and substance use, were not recorded in REAP surveys. Third, psychopathology and drug side-effects were not evaluated with standardized rating instruments. Fourth, the three surveys took place in different centers in some study sites, which may have distorted the longitudinal comparison across centers. Fifth, in this pharmaco-epidemiological project with three separate independent samples, a small proportion of patients might be repeatedly assessed, although the wide time span between the three surveys minimized this possibility. Finally, the clinical decisions driving the use of could not be identified. For example, trazodone could be prescribed for either sleep problems or depressive symptoms in clinical practice. The limitations of this study are partly offset by its strengths that include the large sample size and the ethnic diversity of the sample. Overall, the comparison of the three surveys may approximate trends in the prescription patterns of for schizophrenia inpatients in Asia. In conclusion, the three surveys suggest that although the prescription of for schizophrenia in Asia has gradually increased over the past decade, its frequency is still considerably lower than that in Western settings. There is considerable variation in antidepressant prescription within Asian countries and territories. It is necessary to evaluate the benefits and health risks associated with concomitant use of and antipsychotics in future studies. E85

6 Antidepressants for schizophrenia Y.-T. Xiang et al. Table 2. Commonly prescribed in Asia Total (n = 2,399) (n = 2,136) (n = 2,226) (n = 6,761) % of all patients all patients n all patients n % of all patients n n Trazodone Fluoxetine Fluvoxamine Sertraline Paroxetine Other Table 3. Factors associated with antidepressant prescriptions in the combined sample (n = 6,441). Multiple logistic regression analysis with patients without as the reference group* P-value Odds ratio 95% CI Age (years) < Antipsychotic dose (CPZeq mg/d) Male sex Length of illness (>5 years) Positive symptoms Negative symptoms EPS Benzodiazepines FGAs SGAs Study time 2001 survey survey survey < *Centers in India, Malaysia, and Thailand joined the survey in 2009; therefore, they were not included in multiple logistic regression analysis; study sites have been controlled for. CPZeq, chlorpromazine equivalents; EPS, extrapyramidal symptoms; FGA, first-generation antipsychotic; SGA, second-generation antipsychotic. Acknowledgments This study was supported in part by grants from the National Natural Science Foundation of China ( ; ; ), the Beijing Nova Program of the Beijing Municipal Science and Technology Commission (2008B59), the Chinese University of Hong Kong (Direct Grant for Research; Project ), the Institute of Mental Health Research Grant (CRC 249/ 2008) in Singapore, and the Taiwan Bureau of National Health Insurance (DOH92-NH-1025), Chang Gung Memorial Hospital (CMRPG83043) and the Taipei City Government ( ) in Taiwan. The authors are grateful to the following clinicians involved in the data collection: Hong Deng and Wei Hao in China; Ajit Avasthi, Dipesh Bhagabati, Roy Abraham Kallivayalil, Shubhangi R. Parkar, and Y.C. Janardhan Reddy in India; Tateno Masaru, Masamune Yayoi, Akiyama Tsuyoshi, Sato Soichirou, Nakagome Kazuyuki, Nakamura Jun, and Kuroki Toshihide in Japan; Tae-Yeon Hwang, Seok Hyeon Kim, Yo Wang Lee, and Jong- Il Lee in Korea; Tung-ping Su, Shih-ku Lin, Tzu-Ting Chen, Chieh-Hsin Chang, Hong-Chieh Hsu, Chi-Fa Hung, and Cheng- Chung Chen in Taiwan; Krisakorn Sukavatvibul, Jittima Kleawtanong, Tantawan Suradechasakul, Manote Lotrakul, Usaree Srisutudsanavong in Thailand; and Norharlina Bahar in Malaysia. We also thank Dr Faith B. Dickerson from the Stanley Research Program at Sheppard Pratt, Baltimore, MD, USA; Dr Julie Kreyenbuhl from the Division of Services Research, Department of E86

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