Antipsychotic drug prescription for schizophrenia in East Asia: rationale for change
Dr Mian-Yoon Chong, Department of Psychiatry, Chang Gung Memorial Hospital in Kaohsiung, 123 Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung 83342, Taiwan. Email: firstname.lastname@example.org
Abstract The purpose of this international collaborative study was to investigate the prescription patterns of antipsychotic drugs for schizophrenia in East Asia and to analyze factors that affect these patterns. Prescription patterns for patients admitted for treatment of schizophrenia were surveyed using a standardized protocol from six East-Asian region/countries: China, Hong Kong, Japan, Korea, Singapore and Taiwan. Patients’ social and clinical characteristics, psychiatric symptoms, course of illness, and adverse effects of medications were systematically assessed and recorded. Prescriptions of the first- and second-generation antipsychotic drugs were compared. A total of 2399 patients were recruited. The second-generation drugs comprised 28.1% of all prescribed antipsychotics, and 46% of the antipsychotic prescriptions were in the context of polypharmacy. The mean dosage of antipsychotics for the whole sample was 675.3 + 645.1 mg chlorpromazine equivalents. Japan had a high frequency of prescribing high doses and polypharmacy; Singapore had a high utilization of depot injections while China had a higher prescription of clozapine. Using multiple logistic regression analysis, distinctions in the prescription patterns of antipsychotic drugs were found: first-generation drugs were mainly for controlling aggressive behavior, while second-generation drugs were targeted at the alleviation of positive, negative psychotic symptoms as well as disruptive behavior in schizophrenia. The present collaborative study highlighted differences in the prescription patterns, especially the under-utilization of second-generation antipsychotic drugs in East Asia. The pattern of antipsychotic medication use varied from country to country and is likely to be influenced by the prevailing health-care system, the availability and cost of the drugs.
The concept and treatment modalities of schizophrenia in the past half-century have changed considerably with the discovery of the antipsychotic effects of chlorpromazine and the proposition of the dopamine hypothesis.1 Antipsychotic medications have therefore become the primary treatment for schizophrenia. Of the schizophrenic syndromes, only positive symptoms can be expected to respond to the conventional antipsychotic drugs. They are less effective against negative symptoms and the neurocognitive deficits of schizophrenia.2 At the same time, the limitations of this class of compounds have become painfully apparent, an example being that of extrapyramidal adverse effects such as parkinsonism, dystonia, akathisia and tardive dyskinesia. Moreover, the discomfort and distress produced by these drugs often impel the patients towards non-compliance with treatment, which often leads to psychotic relapse.3
In recent years, numerous putative atypical compounds with novel pharmacologic profiles have been developed to overcome the limitations of the conventional drugs while maintaining superior antipsychotic efficacy.3 These atypical antipsychotic agents, although having better efficacy and effectiveness over the traditional drugs are, however, not widely prescribed in many countries.4 One of the reasons for low utilization of these atypical antipsychotic drugs is that they are expensive, costing up to 10 times more than traditional antipsychotic medications. Even in the USA there were disparities in the use of atypical antipsychotics among the African–Americans, Hispanics and white populations in outpatient prescriptions.5
Prescription habits are affected by a variety of factors, including the health-care system, financing schemes, medical traditions, consumers’ choices, and the overall sociocultural background of the respective countries. In the treatment of schizophrenia, many Western countries have published national guidelines or consensus statements that refer to the prescribing of antipsychotic drugs.6–11 All advise against the use of high dosage other than in exceptional circumstances.7 However, there are discrepancies between these guidelines or algorithms and prescription patterns, and that practice varies substantially according to patient, prescriber and institution.12–13 High-dose prescribing and polypharmacy are not uncommonly seen,14 and it could be regarded as less than perfect by evidence-based standards. There are, however, very few studies examining cross-cultural differences in prescribing practices. The present study aimed to assess the prescription patterns of psychotropic drugs for patients with schizophrenia in East Asia and to determine factors affecting their prescriptions.
Study design and population
Using a standardized protocol, patients diagnosed with schizophrenia who were inpatients between 1 July and 31 July 2001, were surveyed at 32 centers from the following six countries and region: China, Hong Kong, Japan, Korea, Singapore and Taiwan (Table 1). Patients selected for inclusion fulfilled the diagnostic criteria for schizophrenic disorder of the International Classification of Disease, 10th revision (ICD-10)15 or the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).16 The protocol was agreed after five consensus meetings that were held prior to the study to discuss problems related to data collection, conformity of data entry and cross-cultural issues, and was approved by the Research and Ethics Committee of the centers involved. Informed consent was waived because it was an observation study and not related to any experimental use of drugs on humans. The whole project was financially supported by the Japan Society for the Promotion of Science and a grant from the Bureau of National Health Insurance of the Taiwan Department of Health.
Table 1. Clinical patient characteristics
|No. patients||611||108|| 627||442||300||311|
|Centers (total)|| 3|| 1|| 10|| 12|| 1|| 4|
| PH|| 2|| 0|| 9|| 9|| 1|| 2|
| GH|| 1|| 1|| 1|| 3|| 0|| 2|
| Male (%)|| 50.9|| 58.3|| 58.4|| 57.0|| 58.7|| 55.6|
| Female (%)|| 49.1|| 41.7|| 41.6|| 43.0|| 41.3|| 44.4|
| Mean|| 38.5|| 45.36|| 52.87|| 39.11|| 46.24|| 38.23|
| SD|| 12.9|| 13.5|| 13.5|| 9.5|| 10.8|| 10.8|
| Mean|| 61.6|| 63.5|| 58.8|| 61.5|| 57.6|| 65.0|
| SD|| 11.6|| 13.6|| 12.0|| 11.1|| 10.6|| 13.1|
|Duration of illness (%)|
| <1 year|| 11.5|| 0|| 2.7|| 3.9|| 1.3|| 1.0|
| 1–5 years|| 20.4|| 7.4|| 6.7|| 12.0|| 7.3|| 12.8|
| 6–10 years|| 15.1|| 13.9|| 7.9|| 25.8|| 18.3|| 25.7|
| 11–20 years|| 24.8|| 25.9|| 16.9|| 40.7|| 41|| 34.9|
| >21 years|| 28.1|| 52.8|| 65.8|| 17.7|| 32.0|| 25.7|
The design was a cross-sectional survey. Data collected included personal and clinical characteristics, physical condition, duration of illness and significant symptoms for the past month, prescription of all medications and their doses, and adverse effects. The data were collected by the attending psychiatrist of the patient at the time of study in compliance to the protocol set forth. Antipsychotics were divided into first- and second-generation drugs according to the recommendations by the World Psychiatric Association.4 The former included chlorpromazine and all other conventional drugs while the latter consisted of the atypical agents such as clozapine, olanzapine, perospirone, quetiapine, risperidone and zotepine. Other second-generation drugs pending approval (amisulpride, sertindole and ziprasidone) or are currently in phase III of development (aripiprazole, iloperidone) were not included. The classification of antipsychotic drugs on their typical or atypical character is also based on in vivo occupancy of serotonin and dopamine receptors of each drug.17–19
All antipsychotic drugs were converted into chlorpromazine equivalents (CPZeq). The CPZeq are a measure of the relative antipsychotic potencies of neuroleptics. They are generally expressed as a ratio, relative to the arbitrary value of 1, which corresponds to the antipsychotic effects of chlorpromazine. For example, an antipsychotic drug with a CPZeq value of 100 would be 100 times more potent than chlorpromazine. In the present study, conversion of the antipsychotic drugs including perospirone and other atypical drugs into CPZeq was made according to the suggestions by Inagaki et al.20,21 and Bezchlibnyk-Butler and Jeffries.22
Rates of prescribing antipsychotic drugs were first calculated, and the χ2 test was applied to test their differences between countries or region. Doses of antipsychotic drugs were compared using analysis of variance. Finally, multiple logistic regression analyses were applied to assess the independent and interactive effect of various factors that could affect the choice of prescribing first- or second-generation drugs. Each sociodemographic and clinical variable was included in the initial analyses, and only the significant variables in the univariate analyses were included as independent variables to find the model of best fit.
Sociodemographic and clinical characteristics of the sample
A total of 2399 patients was surveyed. China and Japan together comprised more than half of the sample, while only 4.5% of the patient group was from Hong Kong. The majority (83.2%) of the sample was recruited from 23 psychiatric hospitals, while only 16.8% were from eight general hospital psychiatric units. There were more male (55.9%) than female (44.1%) patients, with the male predominance being consistent across the centers (χ2 = 9.17, d.f. = 5, P > 0.1). The age distribution was wide (13–87 years), with a mean age of 43.6 ± 12.5 years. Patients from Taiwan, China, and Korea were younger (38.6 ± 11.4 years) than those from Hong Kong and Singapore (46 ± 11.6 years), while Japan had the oldest age group (52.9 ± 13.5 years; (F = 124.41, d.f. = 5, P < 0.0001). Expectedly, a similar trend was found concerning the duration of illness, with Japanese patients having a longer duration of illness (χ2 = 500.78, d.f. = 30, P < 0.0001) as well as longer periods of hospitalization (F = 197.18, d.f. = 5, P < 0.0001) than patients from other countries (Table 1).
The weight distribution ranged from 32 kg to 114 kg. However, the median weight (61 kg) did not differ between centers (58–63 kg). The most frequent psychiatric symptoms in the whole sample for the past month were social dysfunction (67.8%), delusions (53.2%), hallucinations (44.4%), disorganized speech (30.6%), violence or aggression (24.6%), either verbally (15.5%) or physically (9.1%), and negative symptoms (20%).
Prescription patterns of antipsychotic drugs
There were 2368 patients (98.7%) on antipsychotic pharmacotherapy. Fifty-four percent of them received a single antipsychotic drug, while 46% of them took two or more antipsychotics (polypharmacy). Among the 1273 patients receiving a single antipsychotic drug, 53.3% were given first-generation drugs while 46.7% had second-generation drugs. Of the patients who took two or more antipsychotics, 55.7% received only first-generation drugs, 4.1% had only second-generation drugs, and 40.2% took combinations of first- and second-generation drugs (Table 2).
Table 2. Prescription patterns of antipsychotic drugs in East Asia
| First generation only|| 666|| 28.1|
| Second generation only|| 607|| 25.6|
| First + first|| 610|| 25.8|
| Second + second|| 45|| 1.9|
| First + second|| 440|| 18.6|
Of all antipsychotics prescribed, 71.9% were first-generation and 28.1% were second-generation drugs. Haloperidol (25.0%) was the most frequently prescribed first-generation drug, followed by chlorpromazine (9.7%), levomepromazine (8.7%) and sulpiride (8.4%). The prescription of second-generation drugs varied, with Singapore having the lowest prescription rate (3.6%), followed by Japan (21.5%), Korea (27.1%), Hong Kong (35.2%), Taiwan (42.3%), and China (51.3%). The most frequently prescribed second-generation drug in mainland China was clozapine. Only perspirone (but not clozapine) is marketed in Japan while zotepine is available only in Japan, Korea and Taiwan (Table 3).
Table 3. Prescription of second-generation antipsychotic drugs in East Asia
|Clozapine||243 (62.1)||17 (34)|| 0|| 20 (12.2)|| 5 (25)||63 (41.7)|
|Olanzapine|| 10 (2.6)||24 (48)|| 34 (10.8)|| 29 (17.7)|| 2 (10)||11 (7.3)|
|Quetiapine|| 8 (2.1)|| 2 (4.0)|| 49 (15.5)|| 1 (0.6)|| 0||19 (12.6)|
|Zotepine|| 0|| 0|| 77 (24.4)|| 6 (3.6)|| 0||36 (23.6)|
|Risperidone||130 (33.3)|| 7 (14)||141 (44.6)||108 (65.9)||13 (65)||22 (14.6)|
|Perospirone|| 0|| 0|| 15 (4.7)|| 0|| 0|| 0|
Comparing the prescription of antipsychotics with respect to different settings, general hospital psychiatric units had higher utilization rates of second-generation drugs than psychiatric hospitals (51.1% vs 36.4%, χ2 = 32.6, P < 0.0001). In addition, patients with a length of illness <5 years had higher rates of taking second-generation drugs than those with a length of illness >5 years (39.4% vs 28.6%, χ2 = 26.0, d.f. = 1, P < 0.0001).
Dosage and polypharmacy
One-third of the patients received antipsychotic drugs in the range of 300–599 mg CPZeq. The mean dose for the whole sample was 675.3 ± 645.1 mg CPZeq, with Japan having significantly higher doses (1033.8 ± 884.3 mg) than the other countries or region (F = 72.1, d.f. = 5, P < 0.001; Table 4). Patients with a length of illness >5 years received significantly higher doses (702.1 ± 665.6 mg) than those with a length of illness <5 years duration (534.4 ± 496.8 mg; F = 22.78, P < 0.0001).
Table 4. Comparison of dosages of antipsychotics (mg CPZ eq)
|China (n = 605)||208 (34.4)||291 (48.1)||58 (9.6)|| 30 (5.0)|| 18 (3.0)|| 402.7 (304.2)|
|Hong Kong (n = 103)|| 27 (26.2)|| 30 (29.1)|| 29 (28.2)|| 12 (11.6)|| 5 (4.9)|| 566.3 (646.0)|
|Japan (n = 620)|| 82 (13.2)||132 (21.3)||147 (23.7)|| 72 (11.6)||187 (30.2)||1033.8 (884.3)|
|Korea (n = 439)|| 65 (14.8)||114 (26.0)||123 (28.0)|| 61 (14.0)|| 76 (17.3)|| 763.4 (546.0)|
|Singapore (n = 293)|| 79 (27.0)|| 82 (28.0)|| 51 (17.4)|| 35 (12.0)|| 46 (15.7)|| 664.3 (563.0)|
|Taiwan (n = 308)|| 99 (32.1)||121 (39.3)|| 53 (17.2)|| 18 (5.8)|| 17 (5.5)|| 472.1 (404.2)|
|Total (n = 2368)||560 (23.7)||770 (32.5)||461 (19.5)||226 (9.6)||347 (14.7)|| 675.3 (645.1)|
As for antipsychotic polypharmacy, Singapore (72%) and Japan (79%) had the highest rates. Ninety-five percent of antipsychotic polypharmacy in Singapore involved first-generation drugs including long-acting depot drugs. The use of three or more antipsychotic drugs (up to eight) was predominantly observed in Japanese hospitals, usually a combination of first- and second-generation drugs (93.2%). Significantly higher doses of antipsychotics were given in the polypharmacy group (984.1 ± 755.7 mg) than to patients who were on a single antipsychotic in both the first-generation (460.3 ± 468.22 mg) and second-generation drugs (388.62 ± 216.13 mg; F = 273.71, d.f. = 2, P < 0.0001). Patients with a length of illness >5 years also had a higher proportion of polypharmacy (46.3%) than those with a length of illness <5 years (31.4%).
Prediction of prescribing first- or second-generation drugs
Multiple logistic regression analysis showed that first-generation drugs were used mainly for controlling patients’ aggressive behavior. They were also used more often in psychiatric hospitals and in male patients. There were, however, no interactive effects observed in the analyses (Table 5).
Table 5. Prescription of first- and second-generation antipsychotics: multiple logistic regression analyses
| Constant||−1.57||0.20||61.555||<0.0001|| || |
| Age|| 0.02||0.00||34.495||<0.0001||1.02||1.02–1.03|
| Duration of admission (log)|| 0.13||0.03||23.835||<0.0001||1.14||1.08–1.21|
| Gender (male vs female) || 0.43||0.09||20.653||<0.0001||1.54||1.28–1.85|
| Center (psychiatric vs general hospital)|| 0.58||0.12||22.654||<0.0001||1.79||1.41–2.27|
| Aggression (yes vs no)|| 0.40||0.13|| 9.8412|| 0.0017||1.50||1.16–1.92|
| Constant|| 0.51||0.16||10.357||0.001|| || |
| Delusion (yes vs no)|| 0.47||0.09||29.208||<0.0001||1.60||1.35–1.90|
| Grossly disorganized behavior (yes vs no)|| 0.37||0.11||12.352||0.000||1.45||1.18–1.78|
| Negative symptoms (yes vs no)|| 0.32||0.09||13.011||0.000||1.38||1.16–1.64|
Prescribing patterns of second-generation drugs were entirely different from those of first-generation drugs in that they were determined by the presence of prominent clinical symptoms such as delusions, grossly disorganized behavior or speech and negative symptoms.
The present study demonstrated that there were two distinct rationales for antipsychotic pharmacotherapy in schizophrenia in some East Asian countries: the first-generation drugs were prescribed for controlling aggressive behavior, while second-generation drugs were aimed at the alleviation of psychotic symptoms, notably the positive and negative symptoms, and disorganized behavior. Less than 30% of the prescriptions of antipsychotics for the treatment of schizophrenia in this East Asian sample were for second-generation drugs, a rate that is much lower than in the USA.4
In the present study, prescription patterns of antipsychotic drugs for the treatment of schizophrenia greatly differed between East Asian countries. The variations were largely accounted for by the differences in these countries’ or region's respective health-care policies, preferred treatment modality such as the use of depot or polypharmacy, and the availability and cost of the drugs. For example, Japan has a long history with the national health insurance system, and Japanese patients are usually referred to psychiatric hospitals rather than receiving community treatment. The duration of hospitalization in Japan is generally longer, and psychiatrists prescribe multiple antipsychotic drugs, which thus resulted in higher doses because of the additive effects of two or more antipsychotic drugs prescribed concurrently. A similar practice was also seen in institutions for the long-term care of the chronic mentally ill in the USA.23 The findings are also consistent with a comparison survey of prescription practices for chronic hospitalized schizophrenic patients,24 where Japanese patients were seen among eight countries (Brazil, Hungary, Italy, Japan, Nigeria, Panama, USA, Yugoslavia) that have the highest percentage in receiving simultaneous multiple antipsychotics.
In general, patients with schizophrenia in East Asia, except Japan, received relatively lower doses of antipsychotics than their white counterparts, a finding that is compatible with other studies.25–27 Antipsychotic polypharmacy in Japan was largely due to the combination of first- and second-generation drugs. Occasionally, polypharmacy resulted in the combination of up to seven or eight similar drugs, a practice that needs closer scrutiny.28 With the introduction of second-generation antipsychotic drugs, a review of the practice of high-dose prescribing and antipsychotic polypharmacy is suggested.29 High-dose treatment is not as safe because it may cause problems of cardiac conduction such as torsade de pointes and even sudden death.30 Polypharmacy of antipsychotics also has clear adverse consequences, and is associated with early death.31 The co-prescription of typical (first-generation) antipsychotics with atypical (second-generation) drugs has been shown to increase the frequency of acute extrapyramidal side-effects to levels expected when typicals are used alone.14 The atypical antipsychotics, in contrast, have metabolic and other adverse effects of various degrees that need to be taken into consideration when prescribing.2
The costs of pharmaceuticals are also among the major common factors that affect the prescription of second-generation drugs. The daily cost for second-generation drugs is considerably higher than that of conventional ones, except for clozapine in China, where there are cheap generics. The cost of clozapine is approximately 40-fold higher in Singapore or Taiwan than in China. It is not surprising that the most frequently used second-generation drug in China was clozapine. Clozapine has been extensively used in China in the treatment of resistant and non-resistant schizophrenia longer than in any other East Asian country. Strict regulations for the use of second-generation antipsychotics including clozapine are implemented in other countries, making it difficult to prescribe these drugs. For example in Taiwan, second-generation antipsychotic drugs are recommended only to those who are non-responsive to first-generation drugs, or for older patients, or in the event of prominent adverse effects. These restrictions have been loosened recently because research showed that novel antipsychotic drugs are also effective as first-line medication for schizophrenia.3
The use of conventional antipsychotic drugs for controlling aggressive behavior is an important finding of the present study. Psychomotor slowing, emotional blunting, and affective indifference characterize chlorpromazine and other first-generation antipsychotic drugs,2 also known as ‘major tranquillizers’. It is noteworthy that the earliest effective treatment for schizophrenia with chlorpromazine arose from serendipitous clinical observations rather than systemic studies concerning the scientific neurobiological basis of psychosis or the mechanism of action of antipsychotic agents. In recent years it has become clear that these drugs predominantly suppress the positive symptoms of schizophrenia (i.e. hallucinations, thought disorder, and delusions), but had little or no effect on the negative symptoms (poverty of speech, loss of drive, and flattening of affect).32 Negative symptoms are not only an integral part of the clinical profile of schizophrenia, but can also be induced by antipsychotic drugs.33
In the management of schizophrenia, patients values and expectations are as important as the clinicians’ expertise and evidence-based research findings. To optimize the clinical outcome and enhance patient quality of life, the unique preferences, concerns and expectations that each patient brings to a clinical encounter must be integrated into clinical decisions. To this end, a change of rationale for optimizing treatment in schizophrenia is suggested.
Large-scale surveys of prescribing patterns are often difficult to conduct, especially involving countries with different sociocultural traditions and health-care systems. Other difficulties are related to sampling or other methodological problems such as different assessment tools. In the present study, when the data were pooled together for analysis, the outcome could have been influenced by the countries contributing the most subjects, and there are uneven numbers of subjects of each center.
Despite the aforementioned and other limitations including the lack of quantitative assessment of the schizophrenic symptoms, this collaborative study revealed differences in the prescription patterns, especially the under-utilization of second-generation antipsychotic drugs in East Asia.
The present study was supported by research funds from the Japan Society for Promotion of Science; the International Center for Medical Research, Kobe University, School of Medicine, Kobe, Japan and the Bureau of National Health Insurance, Taiwan (DOH90-NH-010). We are grateful to Dr Yi-Hsin Yang of the Graduate Institute of Oral Hygiene, Kaohsiung Medical University, for her statistical advice.