Clinical and social determinants of psychotropic drug prescription for schizophrenia outpatients in China

Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 756 – 760 www.elsevier.com/locate/pnpbp

Clinical and social determinants of psychotropic drug prescription for schizophrenia outpatients in China Yu-Tao Xiang a,b,⁎, Yong-Zhen Weng b , Chi-Ming Leung a , Wai-Kwong Tang a , Gabor Sandor Ungvari a , Jozsef Gerevich c a

Department of Psychiatry, Chinese University of Hong Kong, Hong Kong SAR, China b Beijing Anding Hospital, Capital Medical University, Beijing, China c Faculty of Orthopedagogics, Eotvos Lorand University, Budapest, Hungary

Received 27 October 2006; received in revised form 31 December 2006; accepted 10 January 2007 Available online 16 January 2007

Abstract To date, few studies have investigated prescription patterns of psychotropic drugs in Chinese patients with schizophrenia in general and outpatients in particular. This study examined the role that socio-demographic and clinical factors play in determining psychotropic drug prescriptions for schizophrenia outpatients in China. Two hundred and fifty-five and 250 clinically stable outpatients with schizophrenia were randomly selected and interviewed in Hong Kong (HK) and Beijing (BJ) respectively, using standardized assessment instruments. Prescriptions of psychotropic drugs for all 505 subjects were collected at the time of the assessment. The relationship between antipsychotic drug prescription patterns and a host of socio-demographic and clinical variables was analyzed and compared between the two study sites. Prescription patterns were quite different for the two ethnically homogenous and clinically very similar samples. In multiple logistic regression analyses, the use of depot antipsychotics (DA) and site (HK vs BJ) both significantly predicted antipsychotic polypharmacy (APP), while symptoms of anxiety, use of clozapine and APP and site predicted use of DA. Age, number of hospitalizations, site, and use of DA predicted use of clozapine. No significant differences were found between the quality of life domains of patients with respect to APP, DA, and clozapine. A complex web of economic and clinical factors and health policies plays an important role in determining psychotropic drug prescription practices for Chinese outpatients with schizophrenia. © 2007 Elsevier Inc. All rights reserved. Keywords: China; Outpatients; Prescription patterns; Schizophrenia

1. Introduction

Abbreviations: AP, antipsychotic drugs; APM, antipsychotic monotherapy; APP, antipsychotic polypharmacy; BJ, Beijing; BPRS, the Brief Psychiatric Rating Scale; CPZeq, chlorpromazine equivalents; DA, depot antipsychotics; HK, Hong Kong; QOL, quality of life. ⁎ Corresponding author. Department of Psychiatry, Shatin Hospital, Shatin, N.T. Hong Kong SAR, China. Tel.: +852 2636 7748; fax: +852 2647 5321. URLs: http://www.cuhk.edu.hk/med/psi/cuhkpsy.html, http://www.bjad.com.cn/home/index.php, [email protected] (Y.-T. Xiang), http://www.bjad.com.cn/home/index.php (Y.-Z. Weng), http://www.cuhk.edu.hk/med/psi/cuhkpsy.html (C.-M. Leung), http://www.cuhk.edu.hk/med/psi/cuhkpsy.html (W.-K. Tang), http://www.cuhk.edu.hk/med/psi/cuhkpsy.html (G.S. Ungvari), http://www.barczi.hu/html/uj/angol/index.html (J. Gerevich). 0278-5846/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2007.01.013

Cross-sectional surveys of prescription patterns for psychiatric patients are an inexpensive, efficient, and fast way of obtaining a global picture of the appropriateness of pharmacotherapy in a given setting (Ungvari et al., 1997). To date, little is known about how clinicians use psychotropic drugs in China, where the characteristics of the mental health system are fundamentally different from those of Western countries. The objectives of the study were: (1) to describe and compare prescription patterns of psychotropic drugs for outpatients with schizophrenia in Hong Kong (HK) and Beijing (BJ), China; (2) to explore the socio-demographic factors that are correlated with use of antipsychotic polypharmacy (APP), depot antipsychotics (DA), and clozapine; (3) to investigate the

Y.-T. Xiang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 756–760

influence of APP, DA, and clozapine on patients’ quality of life (QOL). We hypothesized that (1) significant differences would be found in psychotropic drug prescription patterns between the two sites; (2) the severity of psychotic symptoms would be significantly associated with use of APP, DA, and clozapine; and (3) APP would have a negative effect on QOL while DA and clozapine would favorably influence QOL. 2. Method 2.1. Study settings and subjects The study was conducted in Beijing and Hong Kong. Subjects in HK were randomly selected from patients with schizophrenia who were attending the psychiatric outpatient clinic at a university-affiliated general hospital that has a catchment area with a population of approximately 800,000. Their BJ counterparts, matched according to age, sex, age at onset and length of illness, were recruited from the Adult Psychiatric Outpatient Clinic at Beijing Anding Hospital, another university-affiliated setting covering a population of 3,000,000. Patients who met the following inclusion criteria were invited to participate in the study: 1. diagnosis of schizophrenia according to the DSM-IV (APA, 1994); 2. aged between 18 to 60 years; 3. length of illness ≥ 5 years; 4. outpatients having been clinically stable for at least 3 months before recruitment. Following a recent definition (Lobana et al., 2001), clinical stability was defined as either no change in the medication or other forms of treatment or an increase in the dose of drug(s) by no more than 50% over the past 3 months. The exclusion criteria were: 1. history of or ongoing major chronic medical or neurological condition(s); and 2. significant past or current drug/alcohol abuse other than nicotine. The study was designed and conducted according to the Declaration of Helsinki (Schuklenk, 2001). The study protocol was approved by the Joint CUHK-NTEC Clinical Research Ethics Committee in Hong Kong and the Human Research and Ethics Committee of Beijing Anding Hospital. Written consent was obtained from all subjects.

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Extrapyramidal side effects (EPS) were measured by the Simpson and Angus Scale of Extrapyramidal Symptoms (SAS; Simpson and Angus, 1970) and the Barnes Akathisia Rating Scale (BARS; Barnes, 1989). For the sake of brevity, the sum scores of these scales were entered in the statistical analysis. The 17-item Hamilton Depression Rating Scale (HAM-D; Hamilton, 1960) was used to evaluate the presence and severity of depressive symptoms. QOL was assessed using the Hong Kong and Chinese versions of the World Health Organization Quality of Life Schedule-Brief (WHOQOL-BREF-HK; WHO, 1998) that covers four domains: physical and psychological health, social relationships, and environmental factors. The subjects rated their satisfaction with each item during the past two weeks on a 5-point scale (from 1 = “very dissatisfied” to 5 = “very satisfied”). 2.3. Procedures The principal author assessed all subjects throughout the study. To check the consistency of his ratings, before the study an inter-rater reliability exercise including all clinical rating instruments was conducted with another psychiatrist on 20 randomly selected schizophrenia patients. The intra-class correlation coefficients (ICC) for BPRS overall, positive, negative, and anxiety symptom scores, SAS, BARS, and HAM-D were 0.867, 0.927, 0.92, 0.763, 0.927, 0.835, and 0.935, respectively. 2.4. Statistical analysis Data were analyzed using SPSS Version 13.0 for Windows. The comparison between the two groups with regard to sociodemographic and clinical characteristics was performed by independent samples t-test, Mann–Whitney U test, and chisquare test where appropriate. Multiple logistic regression analysis was carried out to adjust for relevant covariates and to determine the predictors of the use of APP, DA, and clozapine. The level of significance was set at 0.05 (two tailed). 3. Results

2.2. Data collection 2.2.1. Demographic characteristics A questionnaire was designed to collect socio-demographic data and data on the use of all psychotropic drugs. Doses of AP were converted to chlorpromazine equivalents (CPZeq; Kane, 1996; Sim et al., 2004c). Five scales were used as outcome measures in this study. Psychotic symptoms were assessed by the Brief Psychiatric Rating Scale (BPRS; Overall and Beller, 1984). For this study, the following three mean BPRS scores were used: 1. positive symptoms of conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content; 2. negative symptoms of emotional withdrawal, motor retardation, blunted affect, and disorientation; and 3. symptoms of anxiety and tension.

Altogether, 505 patients were involved. Of the 298 (HK) and 288 (BJ) patients who were approached, 43 and 38 patients, respectively, refused participation. There was no significant difference between the study subjects and patients who refused to participate with regard to age, sex, age at onset and length of illness. Table 1 shows the comparison of the subjects’ basic socio-demographic and clinical factors between the two sites. Table 2 shows the variables that were significantly associated with use of APP, DA, and clozapine. There was no significant difference in any of QOL domains between the APP and antipsychotic monotherapy (APM) cohorts before and after controlling for the effect of number of hospitalizations and EPS scores, which were significantly different between the two cohorts. Similarly, no significant difference was found in each of the QOL domains between the DA and non-DA cohorts as

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Table 1 Comparison of prescription patterns for schizophrenia in Beijing (BJ) and Hong Kong (HK) with regard to socio-demographic and clinical variables

Age Age at onset (year) Duration of illness (year) No. of admission BPRS positive BPRS negative BPRS anxiety EPS score Depressive score Physical QOL Psychological QOL Social QOL Environmental QOL CPZeq (mg) Dose of clozapine when only clozapine was taken

Men Covered by insurance On APP On DA On clozapine On anticholinergic On antidepressant On mood stabilizer On benzodiazepine

HK cohort (n = 255)

BJ cohort (n = 250)

Statistics

Mean SD

Mean SD

T/Z

df

P

42.33 26.80 15.45 2.58 1.46 1.45 1.49 0.96 4.68 14.16 13.43 12.99 13.56 256 277

8.88 8.16 8.17 2.55 0.72 0.55 0.63 1.96 3.85 2.45 2.85 2.64 2.31 196 176

43.73 26.93 16.72 2.06 1.40 1.37 1.46 0.42 4.06 14.28 13.86 13.28 13.83 290 233

7.94 7.18 8.35 1.77 0.71 0.56 0.62 1.17 3.99 2.51 2.40 2.64 2.22 178 142

− 1.86 − 0.19 − 1.74 a − 1.71 a 0.82 1.54 0.61 − 3.60 a − 2.85 a − 0.52 − 1.82 − 1.24 − 1.35 − 2.91 a − 0.65 a

503 503

0.06 0.84 0.08 0.09 0.39 0.12 0.54 b0.001 0.004 0.59 0.07 0.21 0.17 0.004 0.51

N

%

N

%

χ2

df

P

122 255 78 92 12 138 21 26 64

47.8 100 30.6 36.1 4.7 54.1 8.2 10.2 25.1

121 207 19 25 75 103 10 8 87

48.4 82.8 7.6 10 30.0 41.2 4.0 3.2 34.8

0.02 47.94 42.99 48.23 56.64 8.44 3.93 9.84 5.67

1 1 1 1 1 1 1 1 1

0.90 b0.001 b0.001 b0.001 b0.001 0.004 0.047 0.002 0.012

503 503 503

503 503 503 503

AP = antipsychotic drug; APP = antipsychotic polypharmacy. a Mann–Whitney U test.

well as the clozapine and non-clozapine cohorts before and after controlling for the effect of confounding variables. 4. Discussion This study compared the prescription patterns of AP between two groups of clinically stable schizophrenia outpatients of the same ethnicity, and explored the socio-demographic and clinical factors that may determine drug prescription. 4.1. Differences between the two sites with respect to prescription patterns The first hypothesis of the study, that significant differences would be found in the prescription patterns of antipsychotic drugs (AP) anticholinergics, mood stabilizers, and antidepressants between the two sites, was supported. Significant differences were found in EPS and depressive symptoms between the two sites, although they were of relatively little clinical significance. They could partly explain the discrepancy in the use of antidepressants and anticholinergic medication. Significant differences remained between the two sites with respect to prescription patterns of APP, DA, clozapine, mood stabilizers and benzodiazepines, although the two samples were comparable in

basic socio-demographic and clinical variables. For this reason, we assume that the diversity of prescription practices might be due to the following non-clinical factors. (1) Insurance coverage. Currently in mainland China, comprehensive health insurance only covers employed patients in urban regions. Therefore, people who fall ill at an early age before obtaining a job, and all residents in rural regions, are rarely covered by health insurance (Phillips et al., 1997). (2) Less stringent drug regulations in BJ than in HK allow for a more liberal prescription of benzodiazepines. (3) Less stringent regulations in HK than in BJ allow for a more liberal prescription of psychotropic polypharmacy. It has been reported that public health policies, the cost of medication, and prescription tradition all affect prescription practices (Sim et al., 2004a). The above speculations need to be replicated or refuted in the future. 4.2. Severity of symptoms and psychotropic drugs Our second hypothesis, that the severity of psychotic symptoms would be significantly associated with use of APP, DA, and clozapine, was only partially confirmed. We found that anxiety in BRPS was negatively associated with use of DA, a finding that was not reported in previous studies. This finding indicates that DA is not advantageous in maintenance treatment of schizophrenia patients with anxiety, while it is more effective for aggressive behavior (Sim et al., 2004d). The association between the use of DA and APP could be explained in part by the lack of flexibility of depot medication in dosing (Barnes and Curson, 1994). While it is justified to temporarily augment depot medication with oral drugs (Ungvari et al., 2002), the combination of DA with oral antipsychotics is hardly justified in clinically stable outpatients. The higher rate of DA in the APP group could also be related to a general principle of traditional Chinese medicine which postulates that the best prescription should contain various ingredients (Binder et al., 1987). In this study, clozapine was less frequently prescribed in the DA group, a practice which is in keeping with current recommendations: to date, there is no strong evidence to suggest the superiority of the combination of clozapine with other antipsychotics (Remington et al., 2005). Table 2 Results of multiple logistic regression analysis: factors associated with the use of APP, depot, and clozapine Use of AP APP

Factor

On DA Site DA Anxiety On clozapine Site On APP Clozapine Age Number of hospitalization Site DA

B

S.E.

P

2.288 1.124 − 0.508 − 1.931 0.866 2.407 − 0.059 0.161

0.270 0.301 0.223 0.646 0.290 0.289 0.016 0.063

b0.001 9.854 b0.001 3.078 0.023 0.602 0.003 0.145 0.003 2.377 b0.001 11.100 b0.001 0.943 0.011 1.175

− 2.185 0.351 b0.001 − 1.728 0.616 0.005

AP = antipsychotic drug; SE = standard error.

Odds ratio

0.112 0.178

95% C.I. 5.806–16.726 1.706–5.553 0.388–0.932 0.041–0.514 1.345–4.200 6.304–19.544 0.913–0.974 1.038–1.329 0.057–0.224 0.053–0.594

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These variations in the use of clozapine between the two sites could have occurred for the following reasons. (1) The availability and cost of the drug and the respective health care policies. In HK, clozapine is expensive (around US$1.2 for 300 mg) and its prescription is under strict control. In contrast, clozapine is one of the cheapest atypical antipsychotic drugs in China (around US$ 0.08 for 300 mg) and regular blood tests are acceptable to most patients. In addition, clozapine use is not strictly controlled by health authorities. (2) Health insurance. Public health insurance policies are quite different between the two sites. In HK, all residents are covered by health insurance. In BJ, atypical antipsychotics, except for clozapine, sulpiride, and risperidone, were not covered by health insurance until October 2005. Therefore, for uninsured patients who are unresponsive to typical antipsychotics, clozapine has been the first choice. In this study, younger age was significantly associated with clozapine use, possibly due to issues related to health insurance. Clozapine prescription was positively associated with the number of hospitalizations mainly due to refractory symptoms.

may reveal the relative trends in prescription practices (Ungvari et al., 2002).

4.3. Quality of life and psychotropic drugs

Acknowledgements

The third hypothesis was that APP would have an inverse impact on QOL, while DA and clozapine would favorably influence QOL. APP could entail higher costs of treatment, higher doses of APs, and higher rates of side effects than APM (Carnahan et al., 2006; Humberstone et al., 2004; Sim et al., 2004b). Accordingly, APP was expected to have an unfavorable effect on QOL in comparison to APM. The advantages of DA are that it can ensure treatment adherence with the potential of delivering the lowest effective dose, thereby decreasing the likelihood of adverse effects (Gerlach, 1995). Hence, DA can be expected to contribute to improve QOL. However, these expectations have not been borne out by our results. One possible explanation for this situation could be that more subtle differences in QOL could not be detected in clinically stable outpatients due to the relative insensitivity of the WHOQOL-BREF.

The authors would like to thank the staff in the Day Hospital at Shatin Hospital, the Li Ka Shing Psychiatric Outpatient Clinic at the Prince of Wales Hospital, and the General Outpatient Department at Beijing Anding Hospital for their assistance in the project.

4.4. Limitations of the study The results should be interpreted with caution. First, the study was cross-sectional, and the causality of relationships found is rather tentative. Second, the results can only be applied to clinically stable schizophrenia outpatients who are living with families in China. Third, the study only involved two of the most developed Chinese cities; therefore, the results may not be applicable to other parts of China with different availability of psychiatric services, cost of treatment, and public health and health insurance policies factors, which all influence the choice of medication. Finally, the conversion of different antipsychotics into CPZ equivalents is a rough approximation at best and lacking sound scientific basis, particularly for atypical antipsychotics (Taylor et al., 2003). However, using the same conversion standard in comparing the two sites could mitigate this limitation and

5. Conclusion This study attempted to examine and compare the role of socio-demographic and clinical factors in determining psychotropic drug prescriptions for 505 clinically stable schizophrenia outpatients in two big cities in China. Psychotropic drug prescriptions were quite different for the two ethnically homogenous and clinically similar samples. The use of DA and study site (HK vs BJ) significantly predicted APP; anxiety, taking clozapine, APP and study site predicted use of DA. Age, number of hospitalizations, study site, and the administration of DA predicted prescription of clozapine. Patients’ QOL was not significantly influenced by APP, or use of DA and clozapine in either site. In addition to clinical factors, general and health economic policies also play an important role in determining psychotropic drug prescription for Chinese outpatients with schizophrenia.

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