Antipsychotic Polypharmacy in Inpatients with Schizophrenia in Asia ( )

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1 Original Paper 7 Antipsychotic Polypharmacy in Inpatients with Schizophrenia in Asia ( ) Authors Y.- T. Xiang 1, 2, C.- Y. Wang 2, T.- M. Si 3, E. H. M. Lee 1, Y.- L. He 4, G. S. Ungvari 5, H. F. K. Chiu 1, S.- Y. Yang 6, M.- Y. Chong 7, C.- H. Tan 8, E.- H. Kua 8, S. Fujii 9, K. Sim 10, K. H. Yong 10, J. K. Trivedi 11, E.- K. Chung 12, P. Udomratn 13, K.- Y. Chee 14, N. Sartorius 15, N. Shinfuku 16 Affiliations Affiliation addresses are listed at the end of the article Key words schizophrenia prescription patterns antipsychotic polypharmacy received revised accepted Bibliography DOI /s Published online ahead of print: 11 October 2011 Pharmacopsychiatry 2012; 45: 7 12 Georg Thieme Verlag KG Stuttgart New York ISSN Correspondence Dr. Y.-T. Xiang Department of Psychiatry Chinese University of Hong Kong Ground Floor, Multicentre Tai Po Hospital Tai Po N. T. Hong Kong Tel.: +852/26/ Fax: +852/26/ Xyutly@gmail.com Introduction Antipsychotic polypharmacy (APP), defined as the concurrent use of 2 or more antipsychotic drugs, is not uncommon in clinical practice [ 1 ], particularly for treatment-resistant schizophrenia patients [2 ]. For example, Medicaid data show that the rate of American schizophrenia patients on APP increased from 3.3 % in 1999 to 13.7 % in 2004 [ 3 ]. Previous studies also found that APP was more common in Asian patients compared with their Western counterparts [4, 5 ]. At the same time, however, to date there has no convincing evidence of improved efficacy for APP. Research support for APP is largely restricted to open-label trials [6 ] rather than double-blind, controlled investigations [3, 7 ]. Further more, some studies found that APP increased adverse effects and the cost of treatment [3, 8 ]. In order to reduce the inappropriate use and maximize the benefits of APP, it is vital to understand how it is being used in clinical practice. In 1999 a large-scale longitudinal, observational, Abstract Objective: This study aimed to identify trends in the use of antipsychotic polypharmacy (APP) and their demographic and clinical correlates in the treatment of schizophrenia in Asia between 2001 and Method: A total of 6761 schizophrenia inpatients in 9 Asian countries and territories were examined; 2399 in 2001, 2136 in 2004, and 2226 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 APP prescription decreased from 46.8 % in 2001, to 38.3 % in 2004, and increased to 43.4 % in 2009, with wide intercountry variations at each survey. Multiple logistic regression analysis of the whole sample revealed that patients on APP were younger, had a higher dose of antipsychotics in chlorpromazine equivalents, and more severe positive and negative symptoms. They were also more likely to receive depot and first-generation antipsychotic drugs. Conclusions: The frequency of APP prescription varied between countries and territories, suggesting that a host of clinical and socio-cultural factors played a role in determining APP use in Asia. To resolve the discrepancy between treatment recommendation and clinical practice, regular reviews of prescription patterns are needed. pharmaco-epidemiological project entitled the Research on Asian Psychotropic Prescription Pattern (REAP) was initiated in 6 Asian countries and territories (China, Hong Kong, Japan, Korea, Singapore, and Taiwan) which surveyed the prescription trends for psychotropic drugs in schizophrenia inpatients in Asia. The first survey conducted in 2001 found that 45.7 % of schizophrenia inpatients in Asia were on APP, with considerable inter-country variation [9 ]. It has been well documented that a complex interplay between health care policies, the availability and cost of drugs, psychiatric training, and preferred treatment modalities strongly influence prescription patterns [9 11 ]. To follow the trend in prescription patterns for schizophrenia and further clarify the use of APP over the past decade, the use of psychotropic medications in the participating Asian countries and territories was surveyed again in 2004 and 2009 using the same research design. This study set out (i) to examine the patterns of APP in schizophrenia inpatients in Asia and the

2 8 Original Paper prescription trends from 2001 to 2009 and (ii) to explore the demographic and clinical correlates of APP with increased power compared with earlier reports [9 ]. Patients and Methods Settings, study design, and subjects The initial survey of REAP project was conducted in July 2001, and was followed by investigations in July 2004 and October 2008 March 2009 using the same design and standardized protocol. India, Malaysia, and Thailand joined the surveys in psychiatric facilities were involved in 2001, 25 in 2004, and 50 in Details of the REAP project have been described elsewhere [9, 10 ]. Briefly, participating patients met the following study criteria: (i) ICD-10 or DSM-IV schizophrenia; (ii) ability to comprehend the aims of the study; and (iii) willingness to provide written or oral consent according to the requirements of the clinical research ethics committees in the respective study sites. Patients suffering from major medical conditions were excluded. The study was approved by the Institutional Review Boards of the respective centers. Consensus meetings on data collection and the uniformity of data entry were held before each survey. Doses of antipsychotic drugs were converted into chlorpromazine equivalent milligrams (CPZeq) [ ]. Socio-demographic and clinical characteristics including age, sex, type and doses of all psychotropic drugs prescribed including antipsychotics, mood stabilizers, antidepressants, anticholinergics and APP, the presence or absence of significant psychiatric symptoms within the past month, and extrapyramidal side effects (EPS), were collected by a review of medical records in 2001, and by either a review of medical records only or a review of medical records supplemented by a patient interview in both 2004 and 2009 using a questionnaire designed for the study. The data were collected by the attending psychiatrists of the patients 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. Comparisons among the 3 cohorts with respect to the proportion of individuals prescribed APP in each study site were conducted using χ-square tests. Comparisons between antipsychotic monotherapy (APM) and APP with respect to socio-demographic and clinical characteristics were performed by independent samples t-test, Mann-Whitney U test, and χ-square test, as appropriate. Multiple logistic regression analysis was used to determine the demographic and clinical variables influencing APP. The 1-sample Kolmogorov-Smirnov test was used to check the normality of distribution for continuous variables. The level of significance was set at 0.05 (2-tailed). Results A total of patients were involved: 2 399, 2 136, and patients in 2001, 2004, and 2009, respectively. Table 1 shows the socio-demographic and clinical characteristics of the whole sample and separately for patients by study site and time of survey. The proportion of APP prescriptions decreased from 46.8 % in 2001 to 38.3 % in 2004 and increased to 43.4 % in 2009, with wide inter-country variations at each survey. In the whole sample there was a significant decrease in the frequency of APP during the period from 2001 to 2009 (χ 2 = 33.3, df = 2, p < 0.001). This decrease was consistently significant in Japan (χ 2 = 44.2, df = 2, p < 0.001). In contrast, a similarly consistent significant increase was seen in China (χ 2 = 19.6, df = 2, p < 0.001). There was no change in Hong Kong (χ 2 = 4.8, df = 2, p = 0.09), Korea (χ 2 = 5.9, df = 2, p = 0.052) and Singapore (χ 2 = 1.3, df = 2, p = 0.05). In Taiwan there was a significant change between the 3 surveys (χ 2 = 26.9, df = 2, p < 0.001), with a decrease in 2004, and then an increase in Fig. 1 presents use of APP in participating countries and regions over the study period. Table 2 shows the prescribing pattern and the number of antipsychotic drugs prescribed in the 3 surveys. The combinations of second-generation antipsychotics (SGAs) and SGAs, first-generation antipsychotics (FGAs) and SGAs increased, while the combination of FGAs and FGAs decreased over time. Table 3 presents the frequently prescribed antipsychotic drugs. Of them, risperidone and clozapine were the most commonly prescribed SGAs, while haloperidol and chlorpromazine were the most commonly prescribed FGAs. Table 4 compares the socio-demographic and clinical characteristics of patients on APM and APP in the whole sample. Patients on APP were older, more often to be men and had higher doses of antipsychotics and more severe positive and negative symptoms. They were also more likely to receive depot antipsychotics, mood stabilizers, anticholinergics and FGAs, while less likely to receive antidepressants. Table 5 displays the independent factors that were independently associated with APP. Patients on APP were younger, had a higher dose of antipsychotics in chlorpromazine equivalents, and more severe positive and negative symptoms. They were also more likely to receive depot and FGAs. Discussion The major finding of this study is that APP was still widely prescribed to more than one third of the schizophrenia patients in this region. In addition, APP decreased in Asia from 46.8 % in 2001 to 38.3 % in 2004, but increased to 42.9 % in The possible reasons for the big drop by 2004 include the continuous education on the cumulative adverse effects caused by APP. The subsequent increase in APP could be explained by the introduction and widespread use of SGAs over the past decade leading to more APP involving SGAs (FGAs + SGAs, or SGAs + SGAs). Given the sample size in Korea, it is probable that the changes (from 35.5 % in 2001 to 37.6 % in 2004 and to 44.4 % in 2009) were clinically, albeit not statistically significant. The frequency of APP in the current sample is broadly in the range of previous findings (12 90 %) in Asian patients [9, 15 ]. For example, APP was found in 17.6 % of 398 randomly selected Chinese schizophrenia outpatients with a significant difference between Beijing (7.1 %) and Hong Kong (28 %) [16 ]. APP figures reported in the present survey are considerably higher than what have been reported for Western patients [17, 18 ], supporting observations that APP is prescribed more commonly for Asian psychiatric patients [4, 5, 19 ]. In recent years a number of clinical pharmacological studies have concluded that there was no substantial proof of improved efficacy for APP, while at the same time this practice could increase adverse effects and the cost of treatment [3, 6, 8 ].

3 Original Paper 9 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 (yea r s ) mean SD C PZe q ( mg / d ) mean SD men ( %) positive symptoms ( %) negative symptoms ( %) EPS ( %) FGA ( %) SGA ( %) APP ( %) % = percentage of all patients *Centers in India, Malaysia, and Thailand joined the survey in 2009; CPZeq = chlorpromazine equivalents; FGA = first-generation antipsychotic; SGA = second-generation antipsychotic; APP = antipsychotic polypharmacy; EPS = extrapyramidal symptoms APP is mainly employed in the treatment of schizophrenia as a last option after other strategies, including clozapine, have failed [20 23 ]. Approximately % of schizophrenia patients experience only partial remission even after co-morbid substance use, life stressors, and medication adherence are well controlled. This seems to be why a significant minority of patients still received APP in this region. However, the rate might be somewhat overestimated because of the cross-tapering of antipsychotic drugs that would temporarily increase the cross-sectional frequency of APP. Another remarkable finding is the considerable variation in APP within Asia. The rates of APP varied from 22.2 % in Taiwan to 78.6 % in Japan in 2001; from 13.2 % in Taiwan to 75.8 % in Singapore in 2004; and from 23.0 % in Hong Kong to 74.0 % in Singapore in A host of biological and socio-cultural factors including genetically determined inter-ethnic differences, psychopharmacological traditions, access to antipsychotic drugs, costs, insurance coverage, and health policy might all contribute to the discrepancy in APP prescriptions [16, 24 ]. With regard to costs, for example, in 2004 the prices of 5 mg haloperidol, 100 mg chlorpromazine, 5 mg olanzapine, and 2 mg risperidone in China were HK$ 0.089, HK$ 0.093, HK$ 26.4, and HK$ 6.2, respectively; the corresponding figures in Hong Kong were HK$ 0.14, HK$ 0.72, HK$ 15.8, and HK$ 9.6 [ 16 ]. As for socio-cultural factors, for example, the general principle of traditional Chinese medicine postulates that the best prescription should be a mixture of various ingredients [ 25 ]. With the study design, the reasons contributing to prescription of APP could not be identified. A more sophisticated design needs to be considered in future REAP surveys. APP was associated with a number of demographic and clinical variables. The associations of APP with age (OR 0.99, 95 % CI ) and antipsychotic doses (0R 1.002, 95 % CI ) were statistically, but not clinically significant. Similar to previous REAP investigations [ 24 ]. APP was more often prescribed for patients with more severe negative and positive psychotic symptoms in this study probably because of the need to optimize the dopamine-2 receptor occupancy and to target a variety of receptors beyond the dopamine-2 receptor [9, 26 ], although this justification for APP lacks robust research data [27, 28 ]. APP was also related to more prescriptions of depot antipsychotics. Because of the lack of flexibility of depot drugs, the practice of temporarily augmenting depot antipsychotics with oral drugs could be justified. First-generation antipsychotics (FGAs) are cheap and readily available across Asia, which could explain why they were more often used in patients on APP. There are a number of limitations to this study. First, as the survey comprised only inpatients, the results cannot be applied to all schizophrenia patients in Asia. Second, some important environmental factors likely to influence appropriate prescription of APP, such as local prescription guidelines, the type of psychiatric facilities and reimbursement policies were not evaluated. In addition, there are differences in health-care schemes, prescribing traditions and treatment guidelines between countries, and even institutions even within one country, such as China and India. The potential confounding effects of these differences need be explored in the future. Third, psychopathology and drug side effects were not evaluated with standardized rating instruments nor was inter-rater reliability assessed prior to the study. Fourth, the conversion of antipsychotic doses into CPZeq is not completely accurate, particularly for SGAs and depot agents [ 29 ]. Fifth, the 3 surveys took place in different centers in some study

4 10 Original Paper Year Fig. 1 Percentage of patients receiving more than one antipsychotic. Percentage China Hong Kong Japan Korea Singapore Taiwan Study site India Thailand Malaysia Average Table 2 Comparison of prescribing pattern of antipsychotics in Asian countries and territories between 2001, 2004 and Prescribing pattern of antipsychotics Statistics n % n % n % χ 2 df p FGA + FGA < SGA + SGA < FGA + SGA < no. of antipsychotics < or more % = percentage of all patients; FGA = first-generation antipsychotic; SGA = second-generation antipsychotic Total n % n % n % n % SG A s Risperidone Clozapine Olanzapine Quetiapine Zotepine Aripiprazole Perospirone Amisulpiride Ziprasidone FG A s Haloperidol Chlorpromazine Levomepromazine Sulpiride Triluoperazine % = percentage of all patients; FGA = first-generation antipsychotic; SGA = second-generation antipsychotic Table 3 The most commonly prescribed antipsychotic drugs in Asia.

5 Original Paper 11 APM group (n = 3 855) APP group (n = 2 906) Statistics Mean SD Mean SD z df P-value age (year) a < antipsychotic dose (CPZeq mg/d) a < N % N % χ 2 df P-value male sex positive symptoms negative symptoms EPS depot antipsychotics < mood stabilizers < antidepressants anticholinergics < FGAs < SGAs a Mann-Whitney U test; CPZeq = chlorpromazine equivalents; APM = antipsychotic monotherapy; APP = antipsychotic polypharmacy; FGA = first-generation antipsychotic; SGA = second-generation antipsychotic; EPS = extrapyramidal symptoms Table 4 Comparison of the antipsychotic polypharmacy (APP) and non-app groups with regard to socio-demographic and clinical characteristics in the combined ( ) sample (n = 6 761). Table 5 Factors associated with antipsychotic polypharmacy in the combined sample (n = 6 441). Multiple logistic regression analysis with antipsychotic monotherapy as the reference group. P-value Odds ratio 95 % C. I. age (year) antipsychotic dose (CPZeq mg/d) < male sex positive symptoms negative symptoms EPS depot antipsychotics < mood stabilizers antidepressants anticholinergics FGAs < study sites China 1.0 Hong Kong < Japan < Korea Singapore Taiwan < 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; CPZeq = chlorpromazine equivalents; APM = antipsychotic monotherapy; APP = antipsychotic polypharmacy; FGA = first-generation antipsychotic; EPS = extrapyramidal symptoms sites, which may have distorted the longitudinal comparison across centers. The limitations of this study are partly offset by its strengths, including the large sample size and the ethnic diversity of the sample. Overall, the comparison of the 3 surveys may approximate trends in the prescription patterns for schizophrenia inpatients in Asia. In conclusion, the findings of the 3 surveys indicate that the prescription patterns of APP for Asian schizophrenia inpatients have fluctuated considerably over the past decade. It is unclear whether this trend was the result of better educational efforts, the distribution of the findings of the first 2 REAP studies in the region and the introduction of more SGAs in clinical practice, or a combination of these and other, yet unknown, factors. Acknowledgements 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 YC 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. The authors also thank clinicians who helped to organize the study in each study site. Conflict of Interest The authors declare no conflict of Interests.

6 12 Original Paper Affiliations 1 Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, P. R. China 2 Beijing Anding Hospital, Capital Medical University, Beijing, P. R. China 3 Peking University, Institute of Mental Health, Beijing, P. R. China 4 Shanghai Mental Health Center, Shanghai, P. R. China 5 The University of Notre Dame Australia, Marian Centre, Perth, Australia 6 Taipei City Hospital, Taipei, Taiwan, ROC 7 Kaohsiung Chang Gung Memorial Hospital and School of Medicine, Chang Gung University, Taiwan, ROC 8 National University of Singapore, Singapore 9 Hyogo Institute for Traumatic Stress (HITS), Kobe, Japan 10 Institute of Mental Health, Buangkok View, Singapore, Singapore 11 Department of Psychiatry, C. S. M. Medical University UP, Lucknow, Uttar Pradesh, India 12 National Seoul Hospital, Seoul, Korea 13 Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand 14 Department of Psychiatry and Mental Health, Tunku Abdul Rahman Institute of Neuroscience, Kuala Lumpur Hospital, Malaysia 15 Association for the Improvement of Mental Health Programs, Geneva, Switzerland, 16 School of Human Sciences, Seinan Gakuin University Fukuoka, Japan References 1 Pickar D, Vinik J, Bartko JJ. Pharmacotherapy of schizophrenic patients: preponderance of off-label drug use. PLoS ONE 2008 ; 3 : e Remington G, Saha A, Chong SA et al. Augmentation strategies in clozapine-resistant schizophrenia. CNS Drugs 2005 ; 19 : Mojtabai R, Olfson M. National trends in psychotropic medication polypharmacy in office-based psychiatry. Arch Gen Psychiatry 2010 ; 67 : Nunley M. Why psychiatrists in India prescribe so many drugs. Cult Med Psychiatry 1996 ; 20 : Phillips M R, Lu S H, Wang RW. 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