Polypharmacy and psychotropic drug loading in patients with schizophrenia in

Asian countries: The REAP-AP4 study

Shu-Yu Yang, PhD,1 Lian-Yu Chen, MD, PhD,1 Eunice Najoan, MD,2 Roy Abraham
Kallivayalil, MD,3 Kittisak Viboonma, MD,4 Ruzita Jamaluddin, MD,5 Afzal Javed,
MD,6 Duong Thi Quynh Hoa, MD,7 Hitoshi Iida, MD,8 Kang Sim, MD,9 Thiha Swe,
MD,10 Yan-Ling He, MD,11 Yongchon Park, MD,12 Helal Uddin Ahmed, MD,13
Angelo De Alwis, MD,14 Helen Fung-Kum Chiu, MD,15 Norman Sartorius, MD,
PhD,16 Chay-Hoon Tan, MD,17 Mian-Yoon Chong, MD, PhD,18 Naotaka Shinfuku,
Accepted Article
MD, PhD,19 Shih-Ku Lin, MD,1,20*

1
Taipei City Hospital and Psychiatric Center, Taipei, Taiwan, 2Mintoharjo Hospital,
Jakarta, Indonesia, 3Pushpagiri Institute of Medical Sciences, Tiruvalla, Kerala,
India, 4Suanprung Psychiatric Hospital, Chian Mai, Thailand, 5Department of
Psychiatry & Mental Health, Hospital Tuanku Fauziah, Kangar, Perlis, Malaysia, 6
Pakistan Psychiatric Research Centre, Fountain House, Lahore, Pakistan, 7Thanh
Hoa Provincial Psychiatric Hospital, Thanh Hoa, Vietnam, 8Department of
Psychiatry, Faculty of Medicine, Fukuoka University, Fukuoka, Japan, 9Institute of
Mental Health, Buangkok Green Medical Park, Singapore, 10 Department of Mental
Health, University of Medicine, Magway, Myanmar, 11Department of Psychiatric
Epidemiology, Shanghai Mental Health Center, Shanghai, China, 12Department of
Psychiatry, Hanyang University, Seoul, Korea, 13National Institute of Mental Health,
Dhaka, Bangladesh, 14National Institute of Mental Health, Angoda, Sri Lanka,
15
Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR,
China, 16Association for the Improvement of Mental Health Programs, Geneva,
Switzerland, 17National University of Singapore, Singapore.18Chiayi Chang Gung
Memorial Hospital and School of Medicine, Chang Gung University, Chiayi, Taiwan,
19
School of Human Sciences, Seinan Gakuin University, Fukuoka, Japan,
20
Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei,
Taiwan

*
Correspondence: Shih-Ku Lin, MD, Taipei City Hospital and Psychiatric Center
309 Songde Road, Taipei 110, Taiwan. E-mail: sklin@tpech.gov.tw
Tel: +88627263141

Running Title: Polypharmacy and PDL in REAP-AP4

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which
may lead to differences between this version and the Version of Record. Please cite this
article as doi: 10.1111/pcn.12676

This article is protected by copyright. All rights reserved.

 Abstract

Aim: The aim of the present study was to survey the prevalence of antipsychotic

polypharmacy and combined medication use across 15 Asian countries and areas in
Accepted Article
2016.

Methods: By using the results from the fourth survey of Research on Asian

Prescription Patterns on antipsychotics (REAP-AP4), the rates of polypharmacy and

combined medication use in each country were analyzed. Daily medications

prescribed for the treatment of inpatients or outpatients with schizophrenia,

including antipsychotics, mood stabilizers, anxiolytics, hypnotics, and antiparkinson

agents, were collected. Fifteen countries from Asia participated in this study.

Results: A total of 3744 patients’ prescription form were examined. The prescription

patterns differed across these Asian countries, with the highest rate of polypharmacy

noted in Vietnam (59.1%) and the lowest in Myanmar (22.0%). Furthermore, the

highest rate and the lowest rate of combined use of mood stabilizers was China

(35.0%) and Bangladesh (1.0%), antidepressants South Korea (36.6%) and

Bangladesh (0%), anxiolytics Pakistan (55.7%) and Myanmar (8.5%), hypnotics

Japan (61.1%) and Myanmar and Sri Lanka (0%), and antiparkinson agents

Bangladesh (87.9%) and Vietnam (10.9%), respectively. The average psychotropic

drug loading of all patients was 2.01 ± 1.64, with the highest and lowest loadings

This article is protected by copyright. All rights reserved.

 noted in Japan (4.13 ± 3.13) and Indonesia (1.16 ± 0.68), respectively.

Conclusion: Differences in psychiatrist training as well as the civil culture and

health insurance system of each country may have contributed to the differences in
Accepted Article
these rates. The concept of drug loading can be applied to other medical field.

Key words: antipsychotic loading, combined medication, polypharmacy,

psychotropic drug loading, schizophrenia

This article is protected by copyright. All rights reserved.

 Introduction

The term polypharmacy is originally coined to refer to problems related to multiple

drug consumption and excessive drug use during treatment of a disease or disorder.1
Accepted Article
In the treatment of schizophrenia, polypharmacy usually refers to the simultaneous

use of two or more antipsychotic medications, and combined (adjunct) medications

as the use of mood stabilizers, antidepressants, anxiolytics, or hypnotics in addition

to single or multiple antipsychotics. Ideally, a clinician should administer

monotherapy of an antipsychotic to treat schizophrenia; however, some proportions

of patients respond to this treatment suboptimally.2 Thus, polypharmacy and

combined medications are frequently applied in clinical practice. The prevalence of

polypharmacy varies among countries: It is lower in North American countries, such

as the United States3-5 and Canada,6 and Europe such as United Kingdom,7 but higher

in Asian countries, such as Japan and Singapore.8, 9 Because it is expensive with

unproven efficacy and several side effects, the use of antipsychotic polypharmacy

used to be discouraged and avoided.10 However, recent data suggested that

antipsychotic polypharmacy and combined medications has been shown to be

helpful in some patients.11, 12

The Research on Asian Prescription Patterns (REAP) is an international

collaborative consortium for studying prescription patterns of psychotropic drugs

This article is protected by copyright. All rights reserved.

 across countries. This consortium has conducted three surveys on antipsychotics

(REAP-AP1, -AP2, and -AP3 in 2001, 2004, and 2009, respectively) and two on

antidepressants (REAP-AD1 and -AD2 in 2004 and 2013, respectively;

Accepted Article
http://reap.asia/index.html). The rate of antipsychotic polypharmacy has been

reported in previous surveys.8, 13 The present study was the fourth REAP survey on

antipsychotics (REAP-AP4), and we report herein on the prevalence of

antipsychotic polypharmacy and combined medication use across 15 Asian countries

and areas.

Methods

Design and participants

For data collection, this study used an online website-based data key-in system. The

research protocol can be accessed at http://reap.asia/reap_ap.html#reap_ap4. In brief,

data on the daily medications prescribed for treating inpatients or outpatients with

schizophrenia, including antipsychotics, mood stabilizers, antidepressants,

anxiolytics, hypnotics, and antiparkinson agents, and demographics were collected.

Fifteen Asian countries and areas, namely China, Hong Kong, Japan, South Korea,

Singapore, Taiwan (REAP-AP1–3), India, Thailand, Malaysia (REAP-AP3),

Bangladesh, Indonesia, Myanmar, Pakistan, Sri Lanka, and Vietnam, participated in

This article is protected by copyright. All rights reserved.

 this study, which took place between March 1, 2016 and May 31, 2016. Because no

established definition of polypharmacy has been reported,14 here we referred to

polypharmacy as the use of two or more antipsychotics, and combined medications

Accepted Article
as the additional use of other psychotropic drugs in the treatment of schizophrenia.

The use of a long-acting injectable antipsychotic combined with the same drug in

oral form was considered monotherapy. The prevalence of antipsychotic

polypharmacy and combined medications of each psychotropic drug were analyzed.

Conventionally, a chlorpromazine equivalent is used to compare the therapeutic

dose of an antipsychotic.15-17 Because newer antipsychotics, such as iloperidone,

lurasidone, and paliperidone, do not have a chlorpromazine equivalent,18 the defined

daily dose (DDD) system is a useful and reliable tool for international drug

utilization studies19 for comparison with either other antipsychotics alone or

combined with other medications. Here, the antipsychotic loading index was

calculated using the sum of the prescribed daily dose (PDD) of each antipsychotic,

divided by its DDD to indicate the quantity of antipsychotic drugs received by a

patient. Accordingly, psychotropic drug loading (PDL) was used to represent the

medication quantity prescribed to treat a mental disorder. For schizophrenia,

psychotropic drugs comprise five pharmacological classes of drugs, namely

antipsychotics, mood stabilizers, antidepressants, anxiolytics, and hypnotics; these

This article is protected by copyright. All rights reserved.

 drugs are administered to treat the core and peripheral schizophrenia symptoms,

such as delusions, hallucinations, agitated or aggressive behaviors, anxious or

depressive mood, and insomnia. PDL is the sum of each psychotropic drug’s PDD
Accepted Article
divided by its DDD in the five pharmacological classes. Based on the dose

information obtained from the Anatomical Therapeutic Chemical (ATC)

Classification System (i.e., the ATC/DDD Index 2016), DDD was considered to be

the assumed average maintenance dose per day for a drug used for its main

indication in an adult weighing 70 kg (https://www.whocc.no/atc_ddd_index/

[accessed 15 September 2016]).20 The ATC/DDD system is a tool used for

exchanging and comparing data on drug use at international, national, or local levels

and has become the gold standard for international drug utilization research. For

instance, if a patient receives a daily dose of aripiprazole 15 mg, valproic acid 750

mg, and lorazepam 2 mg, the PDL will be (15/15) +(750/1500) + (2/2.5) = 2.3. We

calculated the PDL of each enrolled patient and compared the results between

countries.

This REAP-AP4 study was approved by the Institutional Review Board (IRB)

of Taipei City Hospital (TCHIRB-10412128-E) for data collection in this hospital

and management of all data sets. For remaining regions, IRB approval was obtained

from individual study sites.

This article is protected by copyright. All rights reserved.

 Statistical analyses

We used SPSS for Windows (version 20; IBM Corp., Armonk, NY, USA) for
Accepted Article
computing study data. Here, the samples are reported as numbers and percentages as

well as means ± standard deviations (SDs). A chi-square test was then used to

compare the four cohorts of the REAP-AP. Statistical significance was set at p <

0.05.

Results

In total, 3744 patients with schizophrenia (1950 inpatients, 1794 outpatients; 2200

men) were enrolled. The numbers and demographics of each country are presented

in Table 1, where countries are listed in order of the number of patients enrolled. The

mean age was 39.5 ± 13.1 years, with the oldest patients in Singapore (48.1 ± 13.7

years) and the youngest in Bangladesh (31.9 ± 11.0 years). The mean body weight

was 62.9 ± 13.8 kg, with highest patient weights in Hong Kong (71.8 ± 15.4 kg) and

the lowest in Bangladesh (52.2 ± 12.4 kg). The mean body mass index was 23.8 ±

4.6.

Table 2 shows the numbers and rates of antipsychotic polypharmacy and

This article is protected by copyright. All rights reserved.

 combined medication use in each country, with the red and blue cells containing

more than and less than 1 SD, respectively. The antipsychotic polypharmacy rate

ranged from 22.0% (Myanmar) to 59.1% (Vietnam), with a mean rate of 42.2% ±
Accepted Article
12.0%. The mean number of antipsychotics used was 1.5 ± 0.6, with the highest

numbers obtained from Japan (1.8 ± 0.9) and the lowest numbers obtained from

Myanmar (1.2 ± 0.4). The most used antipsychotic was risperidone (36.9%),

followed by olanzapine (20.5%), clozapine (18.5%), haloperidol (15.5%),

chlorpromazine (8.4%), quetiapine (7.9%), aripiprazole (5.6%), and trifluoperazine

(4.0%).

Notably, there was a large variation in the rates of combined medication use

across countries. A comparison of the polypharmacy and drug loading between

inpatients and outpatients is outlined in Table 3.

Figure 1 illustrates the comparison of polypharmacy rates across countries,

from the REAP-AP1 to REAP-AP48, and Figure 2 depicts the comparison of PDL

and antipsychotic loading between the countries. The mean PDL of all patients was

2.01 ± 1.64, with the highest and lowest loadings occurring in Japan (4.1.3 ± 3.13)

and Indonesia (1.16 ± 0.68), respectively.

Discussion

This article is protected by copyright. All rights reserved.

 The mean rate of antipsychotic polypharmacy in Asian countries was 42.2%

(although with considerable variation among the countries), indicating that

Accepted Article
polypharmacy is still widely prescribed for patients with schizophrenia in these

locations compared with Western countries.5-7

Compared with previous REAP-AP surveys8 (45.6% in 2001, 37.4% in 2004,

42.3% in 2009), the rate here showed no apparent significant change. However,

during the course of the four surveys, the rate has consistently decreased to 55.0%

from 78.1% in Japan (χ2 = 60.8, df = 3), to 52.6% from 70.3% in Singapore (χ2 =

22.9, df =3) and to 25.7% from 45.9% in India (χ2 = 24.9, df = 1; all p < 0.001). In

Japan, the use of high doses of antipsychotics and polypharmacy has been

conventionally prevalent.21, 22 To reduce the high rate of polypharmacy, psychotropic

dose equivalence has been suggested for dose standardization; in addition, the public

insurance reimbursement system, drug reduction program, and pharmacist

intervention policies have been revised to improve and prevent psychotropic

polypharmacy.23-25 Our results indicated that the rate of polypharmacy has reduced in

recent years in Japan; nevertheless, among the Asian countries included here, Japan

still has the highest average number of antipsychotic use (1.8 ± 0.9) and

antipsychotic loading (2.29 ± 1.79).

This article is protected by copyright. All rights reserved.

 Notably, the rate of polypharmacy increased only in China, from 25.0% in 2001,

23.2% in 2006, and 35.7% in 2009, to 52.5% in 2016 (χ2 = 63.4, df = 3, p < 0.001).

In a series survey, the frequency of polypharmacy significantly increased from

Accepted Article
26.1% (2002) and 26.4% (2006) to 34.2% in 2012 (p < 0.001) in China.26 The data

analysis in that study revealed that polypharmacy-administered patients and their

families had lower satisfaction with treatment, higher mental quality of life, earlier

onset age, more side effects, and higher antipsychotic doses; the patients were also

more likely to receive first-generation antipsychotics, but less likely to receive

benzodiazepines.

The mean antipsychotic loading was 1.50 ± 1.15 in all patients, which was

approximately equal to chlorpromazine (DDD, 300 mg) 450 mg/day or risperidone

(DDD, 5 mg) 7.5 mg/day. After further stratification (Table 3), inpatients (n = 1950)

showed a significantly higher rate of polypharmacy (49.1%), higher antipsychotic

loading, and more psychotropic loading than did outpatients. These differences were

attributed to higher illness severity among inpatients. Whether a difference exists

between Asian and Western countries in antipsychotic loading should be

investigated in future studies.

The large differences in combined medication use observed among countries

are difficult to explain. For instance, in Bangladesh, only 1 of 99 (1%) patients was

This article is protected by copyright. All rights reserved.

 prescribed mood stabilizers; by contrast, 25.8% and 35.0% of the patients in

Pakistan and China, respectively, were prescribed mood stabilizers. The rate of

antidepressant use was less than 5% in Indonesia, Vietnam, Japan, Myanmar, and
Accepted Article
Bangladesh, but was 23.4%, 25.8%, and 36.6% in Singapore, Hong Kong, and South

Korea, respectively. More than half of the patients in Pakistan (55.7%) and Korea

(54.2%) were receiving anxiolytics, whereas this rate was considerably smaller in

Myanmar (8.5%) and Sri Lanka (9.3%). However, the most notable difference was

observed for the use of hypnotics. In most countries, hypnotics were rarely

prescribed, but the rate of their use was 61.1% and 36.5% in Japan and Taiwan,

respectively. Nevertheless, our pooled combined medication use rates were lower

than those recently reported for 961 patients with schizophrenia from the Eastern

European region (anxiolytics, 70%; antidepressants, 42%; mood stabilizers, 27%).27

Some explanations to account for these differences among countries have been

proposed, such as training backgrounds, availability of drugs, and reimbursement

systems. Although no guidelines have been established for antipsychotic

polypharmacy or combined medications in the treatment of schizophrenia, a subset

of patients still require such unconventional pharmacotherapy.28 In a special

article,29 polypharmacy and high-dose antipsychotics were proposed. Additional

studies are warranted to elucidate the ideal rate of polypharmacy and combined

This article is protected by copyright. All rights reserved.

 psychotropic drug use.

In this study, we created a PDL index to represent the medication burden on

patients with schizophrenia. In the treatment of schizophrenia, we considered each

Accepted Article
class of drug to have the same weighting, in terms of efficacy and side effects. This

is similar to the disease severity assessment of schizophrenia by Positive and

Negative Syndrome Scale,30 in which the item of delusion or hallucinatory behavior,

has the same weighting to the item of anxiety or depression. Notably, Japan had a

higher rate of polypharmacy (55.0%) and the highest index of antipsychotic loading

(2.29 ± 1.79) and PDL (4.06 ± 3.05); by contrast, Vietnam had the highest rate of

polypharmacy (59.1%) and lower antipsychotic loading (1.77 ± 0.96) and PDL (2.09

± 1.11). This example reveals that a high rate of polypharmacy does not necessarily

indicate a high burden of psychotropic drugs. Thus, when reviewing a prescription

pattern in the treatment of schizophrenia, the evaluation of antipsychotic

polypharmacy rate, antipsychotic loading index, and global PDL is crucial.

The PDL index may be applied to any other psychiatric disorder; the concept of

drug loading may be also applied to other diseases, such as hypertension and

diabetic mellitus, where polypharmacy or combined medication use is prevalent.

The main perspectives of the REAP are comparing the differences in

prescription patterns across Asian countries and contributing to the improvement of

This article is protected by copyright. All rights reserved.

 psychotropic drug prescription quality in the Asian countries that participate in this

collaborative consortium. Similar to the conception of a quality indicator project,31,32

a set of indicators can be developed by using these comparisons; the exact positions
Accepted Article
of these indicators can then be learned by clinicians and health administrators to

obtain consistent results. Thus, according to the REAP-AP4 data related to

schizophrenia pharmacotherapy in Asian countries, we suggest the ideal rate of

antipsychotic polypharmacy could be around 30%; the approximate rates in

combination with mood stabilizers, antidepressants, anxiolytics, and hypnotics could

be 15%, 10%, 30%, and 10%, respectively; furthermore, the antipsychotic loading

and PDL could be approximately 1.5 and 2.0, respectively.

In conclusion, the differences in prescription patterns in the treatment of

schizophrenia among countries and fluctuations in the results among the

REAP-AP1–4 may attribute to the diverse training backgrounds of psychiatrists,

civil culture, availability and cost of drugs, patient characteristics, and the local

health care reimbursement system of each country. For a prescriber treating

schizophrenia, the golden rule should be an adequate dose of antipsychotic, reducing

polypharmacy and combined medication as much as possible. The results from all of

the REAP-AP studies provide a basis to compare individual clinicians and countries,

facilitating a more suitable and reasonable prescription pattern. It also offers an

This article is protected by copyright. All rights reserved.

 indicator of change of practice due to changes in the education of psychiatry and

other mental health systems interventions.

Accepted Article
Limitations

This study had several limitations: the convenient sampling method may have

incurred selection bias, patients underwent antipsychotic switching and dose

tapering, the numbers of patients enrolled from each country varied, no stratification

of illness severity was performed, and the ethnic diversity of the sample.

Nevertheless, the comparison of the four surveys may approximate trends of

antipsychotic polypharmacy and combined medications in the treatment of patients

with schizophrenia across Asian countries. Future research should employ a more

precise study design, and also investigate the effects of prescription patterns on

bipolar disorder or other minor psychiatric disorders, particularly by comparing

them with results from Western countries.

Acknowledgements

The authors thank Mr. Da-Yi Tsai for internet server maintenance and Mr. Yan-Lung

Chiou for assistance of data management. The authors are grateful to the following

This article is protected by copyright. All rights reserved.

 clinicians involved in the data collection: Mekhala Sarkar in Bangladesh; Hao Wei

and Weifu Cai in China; Adarsh Tripathi, Ajit Avasthi, Sandeep Grover, Amitava

Dan and Arshad Hussain in India; Andi J Tanra, Elmeida Effendy, Margarita
Accepted Article
Maramis, Khamelia Malik, Isa Multazam, Santi Yuliani, Widodo Sarjana and Metta

Desvini in Indonesia; Toshiya Inada, Hiroaki Kawasaki, Kentaro Kira, Yuma Ogushi,

Shigenobu Kanba, Takahiro Kato, Hiroaki Kubo, Hironori Kuga, Nobutomo

Yamamoto, Futoshi Shintani, Hajime Iwatsuki, Hideki Horikawa and Mina

Sato-Kasai in Japan; Min-Soo Lee, Seon-Cheol Park and Yong-Chon Park in Korea;

Chee Kok Yoon, Loi-Fei Chin, Chee-Hoong Moey, Yee-Tieng Lee, Aida Mohd Arif,

Siong-Teck Wong, Syarifah Hafizah Wan Kassim, Selvasingam Ratnasingam and

Siti Salwa Ramly in Malaysia; Wing Aung Myint, Tin Oo, Bo Bo Nyan, Sun Lin,

Nyan Win Kyaw in Myanmar; M. Munir Hamirani, Imtiaz Dogar and Mazhar Malik

in Pakistan; Ee-Heok Kua and Johnson Fam in Singapore; Samudra Kathiarachchi,

Dulshika Wass and Thilini Rajapakse in Sri Lanka; Chi-Fa Hung, Tsung-Ming Hu,

Chih-Ken Chen, Wen-Chen Ouyang in Taiwan; Pichet Udomratn, Nopporn

Tantirangsee and Pairoj Sareedenchai in Thailand; Tran Van Cuong, La Duc Cuong,

Bui The Khanh, Nguyen Doan Phuong, Ngo Van Vinh, Ly Tran Tinh, Trinh Tat

Thang, Lam Tu Trung, Doan Hong Quang, Duong Thi Quynh Hoa, Trinh Van An

and Cao Tien Duc in Vietnam. We acknowledge Wallace Academic Editing

This article is protected by copyright. All rights reserved.

 (www.editing.tw) for editing this manuscript.

DISCLOSURES STATEMENT
Accepted Article
This work was supported by Taipei City Government (10501-62-012). The authors

declare no conflict of interest in reporting this study.

AUTHOR CONTRIBUTIONS

N.S., M.Y.C., S.Y.Y., C.H.T., N.S., and S.K.L. designed the REAP-AP4 study and

wrote the protocol. L.Y.C., E.N., R.A.K., K.V., R.J., A.J., D.T.Q.H., H.I., K.S., T.S.,

Y.L.H., Y.P., H.U.A., A.D.A., H.F.K.C., recruited participants in different countries,

and S.Y.Y., and S.K.L. performed the statistical analyses and drafted the manuscript.

This article is protected by copyright. All rights reserved.

 References
1. Friend DG. Polypharmacy; multiple-ingredient and shotgun prescriptions.
The New England journal of medicine 1959; 260: 1015-10188.
2. Kane JM, Correll CU. Past and present progress in the pharmacologic
treatment of schizophrenia. The Journal of clinical psychiatry 2010; 71:
Accepted Article
1115-1124.
3. Correll CU, Shaikh L, Gallego JA et al. Antipsychotic polypharmacy: a
survey study of prescriber attitudes, knowledge and behavior. Schizophrenia
research 2011; 131: 58-62.
4. Mojtabai R, Olfson M. National trends in psychotropic medication
polypharmacy in office-based psychiatry. Archives of general psychiatry
2010; 67: 26-36.
5. Fisher MD, Reilly K, Isenberg K, Villa KF. Antipsychotic patterns of use in
patients with schizophrenia: polypharmacy versus monotherapy. BMC
psychiatry 2014; 14: 341.
6. Procyshyn RM, Honer WG, Wu TK et al. Persistent antipsychotic
polypharmacy and excessive dosing in the community psychiatric treatment
setting: a review of medication profiles in 435 Canadian outpatients. The
Journal of clinical psychiatry 2010; 71: 566-573.
7. Kadra G, Stewart R, Shetty H et al. Predictors of long-term (>/=6months)
antipsychotic polypharmacy prescribing in secondary mental healthcare.
Schizophrenia research 2016; 174: 106-112.
8. Xiang YT, Wang CY, Si TM et al. Antipsychotic polypharmacy in inpatients
with schizophrenia in Asia (2001-2009). Pharmacopsychiatry 2012; 45:
7-12.
9. Ito C, Kubota Y, Sato M. A prospective survey on drug choice for
prescriptions for admitted patients with schizophrenia. Psychiatry and
clinical neurosciences 1999; 53 Suppl: S35-40.
10. Stahl SM. Antipsychotic polypharmacy, Part 1: Therapeutic option or dirty
little secret? The Journal of clinical psychiatry 1999; 60: 425-426.
11. Correll CU, Rummel-Kluge C, Corves C, Kane JM, Leucht S. Antipsychotic
combinations vs monotherapy in schizophrenia: a meta-analysis of
randomized controlled trials. Schizophrenia bulletin 2009; 35: 443-57.
12. Stahl SM. Antipsychotic polypharmacy: never say never, but never say
always. Acta psychiatrica Scandinavica 2012; 125: 349-351.
13. Sim K, Su A, Fujii S et al. Antipsychotic polypharmacy in patients with
schizophrenia: a multicentre comparative study in East Asia. British journal
of clinical pharmacology 2004; 58: 178-183.

This article is protected by copyright. All rights reserved.

 14. Freudenreich O, Goff DC. Polypharmacy in schizophrenia: a fuzzy concept.
The Journal of clinical psychiatry 2003; 64: 1132; author reply 1132-1133.
15. Davis JM. Dose equivalence of the antipsychotic drugs. Journal of
psychiatric research 1974; 11: 65-69.
16. Woods SW. Chlorpromazine equivalent doses for the newer atypical
Accepted Article
antipsychotics. The Journal of clinical psychiatry 2003; 64: 663-667.
17. Leucht S, Samara M, Heres S, Patel MX, Woods SW, Davis JM. Dose
equivalents for second-generation antipsychotics: the minimum effective
dose method. Schizophrenia bulletin 2014; 40: 314-326.
18. Leucht S, Samara M, Heres S et al. Dose Equivalents for Second-Generation
Antipsychotic Drugs: The Classical Mean Dose Method. Schizophrenia
bulletin 2015; 41: 1397-1402.
19. Nose M, Tansella M, Thornicroft G et al. Is the Defined Daily Dose system a
reliable tool for standardizing antipsychotic dosages? International clinical
psychopharmacology 2008; 23: 287-290.
20. WHO Collaborating Centre for Drug Statistics Methodology AciwD, 2016.
Oslo, Norway 2015.
21. Takei N, Inagaki A, group J-r. Polypharmacy for psychiatric treatments in
Japan. Lancet 2002; 360: 647.
22. Shinfuku M, Uchida H, Tsutsumi C et al. How psychotropic polypharmacy
in schizophrenia begins: a longitudinal perspective. Pharmacopsychiatry
2012; 45: 133-137.
23. Inada T, Inagaki A. Psychotropic dose equivalence in Japan. Psychiatry and
clinical neurosciences 2015; 69: 440-447.
24. Hashimoto Y, Tensho M. Effect of pharmacist intervention on physician
prescribing in patients with chronic schizophrenia: a descriptive pre/post
study. BMC health services research 2016; 16: 150.
25. Yamanouchi Y, Sukegawa T, Inagaki A et al. Evaluation of the individual
safe correction of antipsychotic agent polypharmacy in Japanese patients
with chronic schizophrenia: validation of safe corrections for antipsychotic
polypharmacy and the high-dose method. The international journal of
neuropsychopharmacology 2014; 18.
26. Li Q, Xiang YT, Su YA et al. Antipsychotic polypharmacy in schizophrenia
patients in China and its association with treatment satisfaction and quality
of life: findings of the third national survey on use of psychotropic
medications in China. The Australian and New Zealand journal of psychiatry
2015; 49: 129-136.
27. Szkultecka-Debek M, Miernik K, Stelmachowski J et al. Treatment patterns

This article is protected by copyright. All rights reserved.

 of schizophrenia based on the data from seven Central and Eastern European
Countries. Psychiatria Danubina 2016; 28: 234-242.
28. Stahl SM. Emerging guidelines for the use of antipsychotic polypharmacy.
Rev Psiquiatr Salud Ment 2013; 6:97-100
29. Moore BA, Morrissette DA, Meyer JM, Stahl SM. Drug information update.
Accepted Article
Unconventional treatment strategies for schizophrenia: polypharmacy and
heroic dosing. BJPsych Bull 2017, 41:164-168.30. Kay SR, Fiszbein A,
Opler LA. The positive and negative syndrome scale (PANSS) for
schizophrenia. Schizophrenia bulletin 1987; 13: 261-276.
31. Arah OA, Westert GP, Hurst J, Klazinga NS. A conceptual framework for the
OECD Health Care Quality Indicators Project. International journal for
quality in health care 2006; 18 Suppl 1: 5-13.
32. Carinci F, Van Gool K, Mainz J et al. Towards actionable international
comparisons of health system performance: expert revision of the OECD
framework and quality indicators. International journal for quality in health
care 2015; 27: 137-146

This article is protected by copyright. All rights reserved.

 Figuure legends

Figuure 1. Compparison of polypharmaccy rates from

m the REAP
P-AP1 to REAP-AP4.
Accepted Article

This article is protected by copyright. All rights reserved.

 Figuure 2. Compparison of psychotropic
p c drug loadiing betweenn countries; red bar
indiicates antipssychotic loaading and bllue bar indicates combined medicaations
loadding.
Accepted Article

This article is protected by copyright. All rights reserved.

Accepted Article
Table 1. Patient number and demographics in each country
South Sri Hong
Indonesia India Taiwan Thailand Malaysia Pakistan Vietnam Japan Singapore Myanmar China Bangladesh Total
n(%) Korea Lanka Kong
n= 581 479 403 322 305 298 274 229 171 164 160 131 99 97 31 3744
gender
Male 370 319 182 212 157 168 184 140 64 107 104 59 58 58 18 2200
( 63.7 ) ( 66.6 ) ( 45.2 ) ( 65.8 ) ( 51.5 ) ( 56.4 ) ( 67.2 ) ( 61.1 ) ( 37.4 ) ( 65.2 ) ( 65 ) ( 45 ) ( 58.6 ) ( 59.8 ) ( 58.1 ) ( 58.8 )
Female 211 160 221 110 148 130 90 89 107 57 56 72 41 39 13 1544
( 36.3 ) ( 33.4 ) ( 54.8 ) ( 34.2 ) ( 48.5 ) ( 43.6 ) ( 32.8 ) ( 38.9 ) ( 62.6 ) ( 34.8 ) ( 35 ) ( 55 ) ( 41.4 ) ( 40.2 ) ( 41.9 ) ( 41.2 )
Age
mean 34.9 36 47.6 39.3 39.3 36.9 38.7 46.5 48.1 37.6 39.7 40.5 31.9 40.4 38.8 39.5
SD 11.3 11.7 11.7 12.3 12.3 11.9 12 14.4 13.7 11.2 16.4 12.5 11.0 13.3 13.9 13.1
Body weight
mean 60.5 64.4 64.9 63.3 67.1 66.3 57.3 64.1 62.5 56.7 67.9 66.7 52.2 57.8 71.8 62.9
SD 12.8 11.9 15.5 13.2 16.5 13.6 10.1 14.2 13.9 10.1 13.0 13.2 12.4 10.2 15.4 13.8
BMI
mean 23.1 24.1 24.8 23.7 25.3 25.2 21.9 23.9 24.7 21.8 24.1 24.2 22.0 22.9 26.3 23.8
SD 4.7 4.4 4.9 4.5 5.1 5.2 3.5 4.3 5.0 3.6 3.8 3.8 4.0 3.4 5.5 4.6

This article is protected by copyright. All rights reserved.

Accepted Article
Table 2. Antipsychotic polypharmacy and combined medications
South Sri Hong
Indonesia India Taiwan Thailand Malaysia Pakistan Vietnam Japan Singapore Myanmar China Bangladesh Total
Korea Lanka Kong
N 581 479 403 322 305 298 274 229 171 164 160 131 99 97 31 3744
Polypharmacy (More than 1 antipsychotic)
N 234 123 109 175 132 154 162 126 90 36 84 60 45 41 9 1580
% (40.3) (25.7) (27.0) (54.3) (43.3) (51.7) (59.1) (55.0) (52.6) (22.0) (52.5) (45.8) (45.5) (42.3) (29.0) (42.2±12.0)
Number of Antipsychotic used
mean 1.4 1.3 1.3 1.7 1.5 1.6 1.6 1.8 1.6 1.2 1.6 1.6 1.5 1.5 1.3 1.5
SD 0.6 0.5 0.5 0.7 0.6 0.8 0.5 0.9 0.6 0.4 0.6 0.8 0.5 0.6 0.5 0.6
Antipsychotic loading (Sum of each antipsychotic’s PDD/DDD)
mean 1.00 1.33 1.39 1.39 1.43 1.79 1.79 2.29 1.47 1.14 1.79 1.92 2.17 1.81 1.44 1.50
SD 0.64 0.92 0.97 1.19 1.07 1.47 1.02 1.79 0.99 0.55 0.95 1.74 1.01 1.34 0.75 1.15
Mood stabilizer used
N 44 34 54 63 18 77 37 69 30 16 56 11 1 7 6 523
% (7.6) (7.1) (13.4) (19.6) (5.9) (25.8) (13.5) (30.1) (17.5) (9.8) (35.0) (8.4) (1.0) (7.2) (19.4) (14.0±9.7)
Antidepressant used
N 24 73 51 62 21 56 12 6 40 5 29 48 0 13 8 448
% (4.1) (15.2) (12.7) (19.3) (6.9) (18.8) (4.4) (2.6) (23.4) (3.0) (18.1) (36.6) 0 (13.4) (25.8) (12.0±10.3)
Anxiolytics used
N 92 151 157 99 49 166 42 73 53 14 24 71 39 9 5 1044
% (15.8) (31.5) (39.0) (30.7) (16.1) (55.7) (15.3) (31.9) (31.0) (8.5) (15.0) (54.2) (39.4) (9.3) (16.1) (27.9±15.2)
Hypnotics used
N 1 7 147 10 1 21 0 140 10 0 4 2 4 0 1 348
% (0.2) (1.5) (36.5) (3.1) (0.3) (7.0) 0 (61.1) (5.8) 0 (2.5) (1.5) (4.0) 0 (3.2) (9.3±17.2)
Antiparkinsonian drug used
N 224 180 154 272 116 207 30 90 69 99 49 65 87 33 13 1688
% (38.6) (37.6) (38.2) (84.5) (38.0) (69.5) (10.9) (39.3) (40.4) (60.4) (30.6) (49.6) (87.9) (34.0) (41.9) (45.1±20.6)
Note: Red and blue cells contain more than and less than 1 SD, respectively.

This article is protected by copyright. All rights reserved.

Accepted Article
Table 3. Comparison of polypharmacy and drug loading between inpatients and outpatient
Inpatient Outpatient P value
Count 1950 1794
Polypharmacy N (%) 957 (49.1) 623 (34.7) < 0.001
Antipsychotic loading mean (SD) 1.72 (1.24) 1.27 (1.01) < 0.001
Psychotropic drug loading mean (SD) 2.29 (1.79 ) 1.70 (1.40) < 0.001

This article is protected by copyright. All rights reserved.