Common Use of High Doses of Antipsychotic Medications in Older Asian Patients with Schizophrenia (2001–2009)

RESEARCH ARTICLE

Common use of high doses of antipsychotic medications in older Asian patients with schizophrenia (2001–2009)

† Yu-Tao Xiang1,2, , Yan Li1, Christoph U. Correll3, Gabor S. Ungvari4,5, Helen F.K. Chiu1, Kelly Y. C. Lai1, † Quan-Sheng Tang6,7, , Wei Hao6, Tian-Mei Si8, Chuan-Yue Wang2, Edwin H. M Lee9, Yan-Ling He10, Shu-Yu Yang11, Mian-Yoon Chong12, Ee-Heok Kua13, Senta Fujii14, Kang Sim15, Michael K.H. Yong16, Jitendra K. Trivedi17, Eun-Kee Chung18, Pichet Udomratn19, Kok-Yoon Chee20, Norman Sartorius21, Chay-Hoon Tan22 and Naotaka Shinfuku23

1Department of Psychiatry, Chinese University of Hong Kong, Hong Kong, China 2Beijing Anding Hospital, Capital Medical University, Beijing, China 3Division of Psychiatry Research, The Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, NY, USA 4School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia 5The University of Notre Dame Australia/Marian Centre, Perth, Australia 6Mental Health Institute, Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China 7Nanning Red Cross Hospital, Nanning, Guangxi Province, China 8The Key Laboratory of Mental Health, Ministry of Mental Health and Peking University Institute of Mental Health, Beijing, China 9Department of Psychiatry, University of Hong Kong, Hong Kong, China 10Department of Psychiatric Epidemiology, Shanghai Mental Health Center, Shanghai, China 11Department of Pharmacy, Taipei City Hospital, Taipei, Taiwan 12Kaohsiung Chang Gung Memorial Hospital and Chang Gung University School of Medicine, Kaohsiung, Taiwan 13Department of Psychological Medicine, National University of Singapore, Singapore, Singapore 14Hyogo Institute for Traumatic Stress (HITS), Kobe, Japan 15Department of General Psychiatry, Institute of Mental Health, Buangkok View, Singapore, Singapore 16Department of Medicine, Alexandra Hospital/Jurong Health Services, Singapore 17Department of Psychiatry, C.S.M. Medical University UP, Lucknow, Uttar Pradesh India 18Department of Psychiatry, National Seoul Hospital, Seoul, Korea 19Department of Psychiatry, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand 20Department of Psychiatry and Mental Health, Tunku Abdul Rahman Institute of Neuroscience, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia 21Association for the Improvement of Mental Health Programs, Geneva, Switzerland 22Department of Pharmacology, National University of Singapore, Singapore, Singapore 23Department of Social Welfare, School of Human Sciences, Seinan Gakuin University, Fukuoka, Japan Correspondence to: Y-T. Xiang, E-mail: [email protected]; W. Hao, E-mail: [email protected]

† Yu-Tao Xiang and Quan-Sheng Tang contributed equally to the paper.

Objective: This study aimed to examine the use of high doses of antipsychotic medications (≥600 mg/day chlorpromazine equivalent) in older Asian patients with schizophrenia and its demographic and clinical correlates. Method: Information on hospitalized patients with schizophrenia aged ≥50 years was extracted from the database of the Research on Asian Psychotropic Prescription Patterns study (2001–2009). Data on 2203 patients in six Asian countries and territories, including China, Hong Kong, Japan, Korea, Singapore and Taiwan, were analyzed. Socio-demographic and clinical characteristics and antipsychotic prescriptions were recorded. Results: The frequency for high-dose antipsychotic medications was 36.0% overall, with 38.4% in 2001, 33.3% in 2004 and 36.0% in 2009. Multiple logistic regression analysis of the whole sample showed that compared to patients receiving low-medium antipsychotic doses, those on high doses had a longer illness duration (odds ratio (OR): 2.0, 95% conﬁdence interval (CI):1.2–3.3, p = 0.008), were more likely in the 50–59-year group (OR: 0.95, 95% CI: 0.94–0.97, p < 0.001), more often had current positive (OR: 1.5, 95% CI: 1.2–1.8, p < 0.001) or negative symptoms (OR: 1.3, 95% CI: 1.03–1.6, p = 0.03), and more commonly received antipsychotic polypharmacy (OR: 5.3, 95% CI: 4.1–6.7, p < 0.001). Extrapyramidal symptoms (p = 0.25) and tardive dyskinesia (p = 0.92) were not more frequent in the high-dose group.

Conclusions: High doses of antipsychotic medications were used in more than one third of older Asian patients with schizophrenia. The reasons for the frequent use of high antipsychotic doses in older Asian patients warrant further investigation. Copyright # 2013 John Wiley & Sons, Ltd.

Key words: schizophrenia; prescription patterns; high dose; older patients; Asia History: Received 27 January 2013; Accepted 17 July 2013; Published online 13 August 2013 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/gps.4011

Introduction large-scale, pharmaco-epidemiological surveys on high antipsychotic doses in older patients with schizophrenia. In the past several decades, the use of high antipsychotic We conducted a secondary analysis of the data from doses has been a continuously controversial topic in the Research on Asian Psychotropic Prescription (REAP) both clinical practice and research (Sim et al., 2009). project. This study set out to (i) examine the prescribing Although most of the studies and treatment recommen- patterns of high doses of antipsychotics (defined as dations do not support this practice, antipsychotic 600 mg/day chlorpromazine equivalent [CPZeq] or drugs are still widely prescribed in high doses in the more)inolderAsianpatients with schizophrenia during – treatment of schizophrenia. For example, 15.4 41% of the period between 2001 and 2009, and (ii) explore the schizophrenia inpatients in the USA (Buchanan et al., demographic and clinical correlates of high-dose 2010; Kreyenbuhl et al., 2010) and in Europe (Webb antipsychotic use in this population. Because of the and Agnew, 1975; Gottlieb et al., 2006) receive high- poorer general health status of older patients and dose antipsychotics. There have been only a few studies heightened vulnerability to psychotropic-induced that examined the prescription patterns of high-dose side effects (Uchida et al., 2009b; Meyers and Jeste, antipsychotics in treatment-refractory schizophrenia 2010), we hypothesized that first, only a small propor- (Kinon et al., 2008; Lindenmayer et al., 2011; Honer tion of Asian older patients would receive high-dose et al., 2012). So far, there has been no convincing antipsychotics, and second, that the proportion of evidence for the improved efficacy of high doses, but high-dose antipsychotic use would significantly the risk of extrapyramidal side effects (Pierre, 2005) decrease over time. and hyperprolactinemia (Byerly et al., 2007) was dose related. In recent years, mortality of schizophrenia has shown Methods a decreasing trend following the general improvement of psychiatric and medical care, enabling many patients Settings, study design and subjects with schizophrenia to live into older adulthood (Kohen et al., 2010). Compared with their younger counter- The REAP project is an ongoing pharmaco-epidemiological parts, older schizophrenia patients are more likely to study of psychotropic drug prescription trends in have drug-induced side effects and poor general health schizophrenia inpatients in Asia. The first REAP study (Uchida et al., 2009b; Meyers and Jeste, 2010); was conducted in July 2001, followed by two waves of therefore, treatment guidelines for younger adult pa- studies in July 2004 and October 2008–March 2009 tients are not entirely applicable to this population. using the same design and standardized protocol. The Age-related pharmacokinetic changes influence drug participating countries and territories included main- absorption and excretion, which may increase the land China (China hereafter), Hong Kong, Japan, susceptibility for antipsychotic-induced adverse effects Korea, Singapore and Taiwan. Centers in India, (Masand, 2000). In contrast to the several treatment Malaysia and Thailand joined the REAP study in guidelines published for adult schizophrenia patients, 2009. Consensus meetings on data collection and uni- we could locate only one set of guidelines for older formity of data entry were held prior to each survey. patients. Alexopoulos et al. (2004) surveyed expert Data of patients who met the following criteria were opinions for recommendations on indications for anti- analyzed in this report: (i) Diagnosis of schizophrenia psychotic use in patients aged 65 years and older. The according to ICD-10 (categories F20) or DSM-IV authors advocated for the use of lower antipsychotic (categories 295.30–295.60) based on a review of medical doses in older patients, for example, 1.25–3.5 mg of records. (ii) Age of 50 years or older. The age cut-off of risperidone, whereas the therapeutic dose of risperidone older patients varied from 50 to 65 years across is 4–8 mg for adult patients. We could not locate any participating institutions according to local cultural

Copyright # 2013 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 359–366 High antipsychotic doses in schizophrenia 361 and professional traditions. In order to make the popu- analysis with the “Enter” method was used to determine lation homogeneous, those aged ≥50 years in the dataset the demographic and clinical variables independently of the REAP project were defined as “older patients” in influencing high antipsychotic doses. Cross-sectional this study. The same age cut-off was also used in other use of high doses (defined as 600 mg/day CPZeq or recent studies (Dassori et al., 2011). (iii) Taking antipsy- more) was the dependent variable, while independent chotic drugs. And (4) ability to understand the study variables included participating countries and time, age, aims if interviewed. Patients with major medical condi- gender, psychotic symptoms, duration of illness, use of tions affecting the cardiovascular, respiratory, digestive, first-generation antipsychotics (FGAs), ACMs and anti- hematological, endocrine, urinary, connective tissue psychotic polypharmacy, as well as the presence of EPS and nervous systems were excluded. Doses of antipsy- and TD. The level of significance was set at 0.05 (two chotic drugs were converted into CPZeq mgs (APA, tailed). 1997; Kane et al., 1998; Woods, 2003). Socio-demographic and clinical characteristics of Results eligible patients, including age, sex, duration of illness, type and doses of antipsychotics and anticholinergic Sample description medications (ACMs), psychotic symptoms in the past month, and extrapyramidal side effects (EPS: Parkin- Altogether, 31 psychiatric institutions were involved in sonism, akathisia, acute and tardive dystonia, and 2001, 25 in 2004 and 50 in 2009. A total of 6761 dykinesia) were collected by a review of medical records patients participated at the three time points of the in 2001 and by either a review of medical records only REAP study. Of these, 2236 (33.1%) fulfilled the or a review of medical records supplemented by an current report’s entry criteria and were eligible for interview in 2004 and 2009. Tardive dyskinesia (TD) is inclusion in the analyses. Because there were only 15 treated separately from the other forms of EPS because patients in India, 14 in Malaysia and 8 in Thailand, of its different clinical characteristics and relevance. these three sites were not included in the analyses. The data were collected by the attending psychiatrists Hence, 2203 patients were included in the analysis: or by members of the research team with the agreement 800 in 2001, 670 in 2004 and 733 in 2009. of the patients’ treating psychiatrists. In the REAP Table 1 presents the socio-demographic and clinical project, psychotropic drugs are categorized according characteristics of the whole sample and separately by par- to the World Health Organization Anatomic Therapeu- ticipating country/area. The mean age of the sample was tic Chemical (WHO-ATC) system (WHO Collaborat- 58.9+/À7.5 years old (range: 50–87 years). Altogether, ing Centre for Drug Statistic Methodology, 2002; 55.5% of the patients were male. In total, 62.7% of the Chong et al., 2010). Antipsychotic polypharmacy was patients received FGAs (78.4% in 2001, 63.1% in 2004 defined as the concurrent use of two or more and 45.3% in 2009) and 58.8% received second-generation antipsychotic drugs. ACMs included trihexyphenidyl, antipsychotics (SGAs) (39.0% in 2001, 62.1% in 2004 biperiden, benztropine, promethazine, procyclidine, and 77.5% in 2009). The 10 most frequently used amantadine, piroheptine and mazaticol. antipsychotics were risperidone (28.0%), haloperidol The study protocol was approved by the clinical (25.7%), chlorpromazine (19.7%), levomepromazine research ethics committees of the respective centers. (14.8%), clozapine (10.8%), olanzapine (9.8%), sulpiride Given the anonymous nature of this observational (8.4%), quetiapine (7.9%), zotepine (6.7%) and flu- study and the minimal risk to patients, informed con- phenazine decanoate (3.9%). Figure 1 depicts the use sent was deemed unnecessary at some study sites in of high-dose antipsychotics in older patients of the line with the requirements of the local clinical research REAP project over the study period. Of patients in the ethics committee (Shinfuku and Tan, 2008) if only a six participating countries and territories, those in Japan review of case notes was used. All patients participat- were more likely to receive high doses of antipsychotics. ing in the interview provided written or oral consent according to the requirements of the Clinical Research Ethics Committee in the respective study sites. High-dose antipsychotic use

A total of 794 (36.0%) of the 2203 patients received Statistical analysis antipsychotic drugs in high doses in the three REAP surveys: 307 in 2001 (38.4%), 223 in 2004 (33.3%) ThedatawereanalyzedusingSPSS 19.0 for Windows and 264 in 2009 (36.0%). High-dose antipsychotic (SPSS Inc., Chicago, IL, USA). Multiple logistic regression use occurred in 536 (39.7%) patients in the 50- to

Copyright # 2013 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 359–366 Copyright 362 # 03Jh ie os Ltd. Sons, & Wiley John 2013

Table 1 Socio-demographic and clinical characteristics of older Asian patients with schizophrenia in REAP surveys 2001–2009

China Hong Kong Japan Korea Singapore Taiwan Total (n = 413) (n = 75) (n = 1046) (n = 238) (n = 150) (n = 281) (n = 2203)

Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD Mean SD

CPZeq (mg/day) 452.2 347.1 422.2 342.4 677.1 628.8 630.3 596.7 472.5 442.6 447.2 349.7 577.9 541.3 N % N % N % N % N % N % N % Age group (years) 50–59 339 82.1 48 64.0 460 44.0 181 76.1 99 66.0 222 79.0 1349 61.2 60–69 62 15.0 20 26.7 393 37.6 51 21.4 46 30.7 48 17.1 620 28.1 70 and older 12 2.9 7 9.3 193 18.5 6 2.5 5 3.3 11 3.9 234 10.6 Duration of illness (≥5 years) 39 9.4 6 8.0 28 2.7 11 4.6 13 8.7 16 5.7 113 5.1 Men 233 56.4 41 54.7 575 55.0 124 52.1 81 54.0 168 59.8 1222 55.5 Presence of positive symptoms 209 50.6 53 70.7 706 67.5 164 68.9 73 48.7 190 67.6 1395 63.3 Presence of negative symptoms 287 69.5 45 60.0 753 72.0 125 52.5 52 34.7 163 58.0 1425 64.7 Presence of EPS 69 16.7 44 58.7 330 31.5 72 30.3 19 12.7 108 38.4 642 29.1 Presence of TD 17 4.1 14 18.7 90 8.6 17 7.1 6 4.0 33 11.7 177 8.0 On FGAa 163 39.5 37 49.3 761 72.8 174 73.1 123 82.0 124 44.1 1382 62.7 On SGAb 305 73.8 37 49.3 653 62.4 106 44.5 16 10.7 179 63.7 1296 58.8 Antipsychotic polypharmacy 116 28.1 32 42.7 712 68.1 89 37.4 99 66.0 51 18.1 1099 49.9 Anticholinergics 151 36.6 39 52.0 800 76.5 132 55.5 108 72.0 155 55.2 1385 62.9 High dose of antipsychotics 117 28.3 16 21.3 455 43.5 83 34.9 42 28.0 81 28.8 794 36.0

CPZeq, chlorpromazine equivalents; EPS, extrapyramidal symptoms; TD, tardive dyskinesia; FGA, ﬁrst-generation antipsychotic; SGA, second-generation antipsychotic. n eit Psychiatry Geriatr J Int aAny use of FGA. bAny use of SGA. 2014; .T Xiang Y.-T. 29 359 : tal et – 366 . High antipsychotic doses in schizophrenia 363

Figure 1 Percentage of older patients with schizophrenia receiving high doses of antipsychotic medications.

59-year group, 206 (33.2%) in the 60- to 69-year Table 2 Demographic and clinical correlates independently associated group and 52 (22.2%) in the 70-year and older group. with high doses of antipsychotics in older inpatients with schizophrenia (n = 2203)

Correlates of high-dose antipsychotic use p value Odds ratio 95% CI

Age group (years) Table 2 shows the factors that were independently asso- 50–59 – 1.0 – ciated with high antipsychotic doses. Compared to pa- 60–69 <0.001 0.5 0.4, 0.7 tients receiving low-medium antipsychotic doses, 70 and older <0.001 0.4 0.2, 0.5 Duration of illness (≥5 years) 0.008 2.0 1.2, 3.3 those on high doses had a longer illness duration (odds Male sex 0.17 1.2 0.9, 1.4 ratio (OR): 2.0, 95% confidence interval (CI):1.2–3.3, Positive symptoms <0.001 1.5 1.2, 1.8 p = 0.008), were more likely in the 50–59-year group Negative symptoms 0.03 1.3 1.03, 1.6 – < EPS 0.25 0.9 0.7, 1.1 (OR: 0.95, 95% CI: 0.94 0.97, p 0.001), more often TD 0.92 1.0 0.7, 1.4 had current positive (OR: 1.5, 95% CI: 1.2–1.8, p < 0.001) On FGA 0.48 1.1 0.8, 1.4 or negative symptoms (OR: 1.3, 95% CI: 1.03–1.6, Antipsychotic <0.001 5.3 4.1, 6.7 polypharmacy p = 0.03), and more commonly received antipsychotic Anticholinergics 0.25 1.1 0.9, 1.4 polypharmacy (OR: 5.3, 95% CI: 4.1–6.7, p < 0.001). Participating countries/areas China – 1.0 – Hong Kong 0.06 0.5 0.3, 1.02 Discussion Japan 0.31 1.2 0.9, 1.6 Korea 0.52 1.1 0.8, 1.7 Singapore 0.008 0.5 0.3, 0.8 There is no agreement on the definition of what Taiwan 0.36 1.2 0.8, 1.7 constitutes high doses of antipsychotic drugs. The com- Study time 2001 survey – 1.0 – monly agreed cut-offs are 600 mg or 1000 mg CPZeq 2004 survey 0.14 0.8 0.7, 1.1 (Alvarez and Ayas, 2004; Sim et al., 2009). Because of 2009 survey 0.87 1.0 0.8, 1.3 the age-related changes in renal excretion and hepatic metabolism in the older patients and the fact that Asian Multiple logistic regression analysis with non-high dose of antipsy- patients require lower doses of antipsychotics and that chotics as the reference group. There was co-linearity between the use of FGA and SGA; therefore, they are more sensitive to EPS than their Western coun- use of SGA was not included in multiple logistic regression analysis. terparts (Chiu et al., 1991; Frackiewicz et al., 1997), the CPZeq, chlorpromazine equivalents; EPS, extrapyramidal symp- lower cut-off of ≥600 mg CPZeq for high dose was toms; FGA, first-generation antipsychotics; TD, tardive dyskinesia.

Copyright # 2013 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 359–366 364 Y.-T. Xiang et al. chosen for this study. The Schizophrenia Patient Out- although compelling evidence for this practice is lacking comes Research Team Psychopharmacological Treat- (Kreyenbuhl et al., 2010). Also, clinicians may be able to ment Recommendation suggested 300–1000 mg/day strictly monitor and promptly deal with antipsychotic- CPZeq for acute and 300–600 mg/day for maintenance induced side effects in inpatient settings, which allows treatment (Ayas et al., 2003). In most Asian countries, them to prescribe higher doses more safely. This seems a sizeable number of clinically stable schizophrenia to be supported by the lack of a significant association patients continue to receive maintenance treatment in between high-dose treatment and EPS or TD in our psychiatric hospitals because of the under-developed cross-sectional surveys. Further, there is a lack of community psychiatric services (WHO, 2005; Shinfuku specific treatment guidelines for older schizophrenia and Tan, 2008). This was another reason why this study patients. As a result, many psychiatrists may rely on defined ≥600 mg CPZeq as a high antipsychotic dose for clinical wisdom derived from treating younger adults, Asian older inpatients. There was no uniform age cut- while ignoring the fact that older patients usually need off for older patients in Asian countries. In this study, or are sufficiently helped by lower antipsychotic doses patients aged 50 years and older were defined as “older (Uchida et al., 2009a, 2009b). patients,” which explains the mean age of 58.9 years in Multivariate analysis revealed that high antipsychotic the sample. doses were independently correlated with longer illness To the best of our knowledge, this is the first duration, a higher likelihood of clinically present posi- international study that surveyed the use of high-dose tive or negative symptoms, younger age and more antipsychotic drugs in older schizophrenia patients. frequent use of antipsychotic polypharmacy. The asso- The result did not support our first hypothesis that ciation between younger age and high antipsychotic only a small proportion of older patients would dose observed in this survey is consistent with earlier receive high doses; the 36% found in this study is findings (Gottlieb et al., 2005; Gottlieb et al., 2006). comparable to Western findings of 15.4–41% in Younger patients may tolerate higher antipsychotic non-older adult patients (Webb and Agnew, 1975; doses better and often present with more aggressive be- Buchanan et al., 2010; Kreyenbuhl et al., 2010). The havior (Alexopoulos et al., 2004), which could possibly percentage of high antipsychotic doses was particu- explain this association. High antipsychotic doses were larly prominent in Japan (43.5%) compared with the often used in patients with more severe psychotic symp- other study sites (21.3–34.9%). Based on the current toms (Webb and Agnew, 1975; Ji, 2005), a finding rep- study design, we cannot identify the reasons for the licated in this survey. Hospitalized patients with longer common use of high antipsychotic doses in Japan, illness duration often present with treatment-resistant except for assuming that probably clinical traditions symptoms, which could possibly account for the rela- might play an important role, including the frequent tionship between longer illness and high antipsychotic use of antipsychotic polypharmacy in Japan (Gallego dose, which was also reported in a previous study et al., 2012; Kishimoto et al., 2013). Moreover, it has (Merecz et al., 2006). Antipsychotic polypharmacy, a been reported that sometimes sedation was the common clinical practice, especially in Asia (Gallego primary purpose of pharmacotherapy for schizophrenia et al., 2012) (Gallego et al., 2012), was closely associated inpatients in Japan (Fujii and Shinfuku, 2005; Shinfuku with high antipsychotic doses, confirming earlier find- and Tan, 2008), which, to some extent, may also explain ings (Correll et al., 2009). The lack of a significant asso- the frequent use of high antipsychotic doses. ciation between high-dose treatment and EPS or TD The second hypothesis that the proportion of high could possibly be explained by the frequent use of SGAs antipsychotic doses would significantly decrease over (59.1% in the high-dose group vs. 58.7% in the low-me- time was not supported either. The prescribing trend dium-dose group); SGAs are less likely to cause EPS and for older Asian patients did not significantly change TD in contrast to FGAs (Alexopoulos et al., 2004; (38.4% in 2001 vs. 33.3% in 2004 vs. 36.0% in 2009). Correll et al., 2004). Several reasons could account for the prescription of The strengths of this study include its large sample persistently high antipsychotic doses. The REAP surveys size, the number and variety of participating sites focused only on inpatients, and some of them have involved, and the relatively wide time span between more severe and enduring psychotic symptoms. In fact, the three surveys. Yet, there are several limitations the results from the multivariate analyses support this that reduce the generalizability of the results. First, notion. Moreover, a considerable number of these the study only targeted hospitalized patients in patients may have had only partial or no response to selected Asian countries in this large continent with low or moderate antipsychotic doses; consequently, a great variety of socio-cultural and economic con- they were prescribed higher than standard doses, texts and differences in mental healthcare cultures

Copyright # 2013 John Wiley & Sons, Ltd. Int J Geriatr Psychiatry 2014; 29: 359–366 High antipsychotic doses in schizophrenia 365 and traditions. In addition, because of logistic rea- Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, sons, the diagnoses were only made by reviewing Gerson Lehrman Group, IntraCellular Therapies, medical records; the severity of psychotic symptoms Lundbeck, Medavante, Medscape, Merck, National and EPS were assessed by dichotomous variables, Institute of Mental Health, Janssen/J&J, Otsuka, rather than standardized diagnostic instruments with Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva rater training and established inter-rater reliability. and Vanda. He has received grant support from Second, the data were collected by a chart review in BMS, Feinstein Institute for Medical Research, 2001 and by either a review of case charts or patient Janssen/J&J, National Institute of Mental Health interviews in 2004 and 2009, which might have led (NIMH), National Alliance for Research in Schizo- to a certain observational bias. Third, because of the phrenia and Depression (NARSAD), and Otsuka. He cross-sectional design, thecausalitybetweenhigh has been a Data Safety Monitoring Board member doses and demographic and clinical factors could forCephalon,EliLilly,Janssen,Lundbeck,Pfizer, not be explored. Fourth, psychotic symptoms and Takeda and Teva. The remaining authors had no drug-induced side effects were not assessed with conflicts of interest in conducting this study or standardized rating instruments. Fifth, the number preparing the manuscript. of participating institutions changed across different REAP surveys. The participants’ basic socio-demographic characteristics and the sample size in each country/region were not matched be- Key points tween different surveys, which may have influenced the results. Sixth, a host of important variables that • To date, no international studies have investigated likely influence prescription patterns, such as the the prescribing patterns of high doses of duration of antipsychotictreatmentpriortothe antipsychotic medications in older Asian patients study, drug interactions, smoking and mental with schizophrenia. healthcare policies, were not evaluated or could not be • The results suggest that the prescription of high included in the analyses because of too many missing doses of antipsychotic medications for one data. Finally, the conversion of antipsychotic doses into third of older schizophrenia inpatients in Asia CPZeq is not accurate, particularly for SGAs. However, is common. using the same conversion standard when comparing • Continuing education and training addressing two samples (e.g., lower vs. higher dose groups) in the the rational use of high doses of antipsychotic multivariate analysis can mitigate this limitation and medications is necessary in Asian countries. may reveal relative trends in prescribing practices (Ungvari et al., 2002). In conclusion, the findings of this survey, spanning three time points between 2001 and 2009, show that high antipsychotic doses are common in older Asian Acknowledgements patients with schizophrenia and that this prescribing trend did not decrease over the first decade of this The authors are grateful to the following clinicians century despite lack of compelling evidence for this involved in the data collection: Hong Deng in China; practice (Kreyenbuhl et al., 2010). In order to maxi- Ajit Avasthi, Dipesh Bhagabati, Roy Abraham mize the safety and tolerability of pharmacological Kallivayalil, Shubhangi R. Parkar and Y. C. Janardhan treatment in this high-risk patient population, the rea- Reddy in India; Tateno Masaru, Masamune Yayoi, sons for the frequent use of high antipsychotic doses Akiyama Tsuyoshi, Sato Soichirou, Nakagome in older Asian patients and for the considerable differ- Kazuyuki, Nakamura Jun and Kuroki Toshihide in ences across countries need to be explored in future Japan; Tae-Yeon Hwang, Seok Hyeon Kim, Yo Wang studies using more sophisticated methodologies. 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 Conflicts of interest Taiwan; Krisakorn Sukavatvibul, Jittima Kleawtanong, Tantawan Suradechasakul, Manote Lotrakul and Dr. Correll has been a consultant and/or advisor to or Usaree Srisutudsanavong in Thailand; and Norharlina has received honoraria from Actelion, Alexza, Ameri- Bahar in Malaysia. The authors also thank clinicians can Academy of Child and Adolescent Psychiatry, who helped to organize the study in each study site.

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