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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 35  |  Issue : 2  |  Page : 82-89

Prescription patterns and trends of anxiolytics and hypnotics/sedatives among child and adolescent patients with psychiatric illnesses in a psychiatric center of northern Taiwan


1 Department of Pharmacy, Taoyuan Psychiatric Center, Taoyuan City, Taiwan
2 Department of General Psychiatry, Taoyuan Psychiatric Center, Taoyuan City, Taiwan
3 Department of General Psychiatry, Taoyuan Psychiatric Center, Taoyuan City; Department of Psychiatry, School of Medicine, National Taiwan University Hospital and School of Medicine, National Taiwan University, Taipei, Taiwan

Date of Submission02-Apr-2021
Date of Decision11-Apr-2021
Date of Acceptance12-Apr-2021
Date of Web Publication22-Jun-2021

Correspondence Address:
M.D., Ph.D Hung- Yu Chan
No. 71, Long-Show Street, Taoyuan City 330
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tpsy.tpsy_18_21

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  Abstract 


Background: The prevalence of prescriptions of anxiolytics and hypnotics/sedatives for child and adolescent patients with psychiatric illnesses is increasing over the world. No studies exist to focus on the prescription trends and patterns of anxiolytics and hypnotics/sedatives for child and adolescent patients in psychiatric hospitals of Taiwan. Methods: In this retrospective study for all outpatients who were equal or younger than 18 years of age in a psychiatric service, we collected related study variables from the study psychiatric services from 2006 to 2015. Reviewing the electronic medical information system, we extracted both patients' demographic or clinical data (such as sex, age, as well as psychiatric diagnoses), and prescriptions of anxiolytics and hynotics/sedatives. Results: During the study period, the proportion of patients received anxiolytics and hypnotics/sedatives was decreased significantly (from 9.16% in 2006 to 5.85% in 2015, p < 0.001). The proportion of patients received anxiolytics was significantly decreased (from 5.34% in 2006 to 4.54% in 2015, p > 0.05), while hypnotics/sedatives was also decreased significantly (from 5.35% to 2.27%, p < 0.001). Logistic regression analysis showed that the use of anxiolytics and hypnotics/sedatives was significantly associated with age (p < 0.001), gender (p < 0.001), patients' status of catastrophic illnesses (p < 0.001), and diseases (p < 0.001). Conclusion: Anxiolytics and hypnotics/sedatives have the rôles in the treatment of child and adolescent patients with psychiatric Illnesses. Clinicians should be aware of the adverse events of these medications and prescribe them carefully for this population. Certainly, we need more well-designed clinical studies to study the safety and efficacy of anxiolytics and hypnotics/sedatives medications for children and adolescents.

Keywords: benzodiazepines, gender, psychiatric illnesses, status of catastrophic illnesses


How to cite this article:
Cheng SW, Sun HJ, Chan HY. Prescription patterns and trends of anxiolytics and hypnotics/sedatives among child and adolescent patients with psychiatric illnesses in a psychiatric center of northern Taiwan. Taiwan J Psychiatry 2021;35:82-9

How to cite this URL:
Cheng SW, Sun HJ, Chan HY. Prescription patterns and trends of anxiolytics and hypnotics/sedatives among child and adolescent patients with psychiatric illnesses in a psychiatric center of northern Taiwan. Taiwan J Psychiatry [serial online] 2021 [cited 2021 Oct 24];35:82-9. Available from: http://www.e-tjp.org/text.asp?2021/35/2/82/318962




  Introduction Top


Anxiolytics and hypnotics/sedatives were introduced into clinical practice in the early 1960s. For the next 20 years, those drugs were among the most frequently prescribed medications due to their effectiveness and safety, both alone and in combination with other drugs. This was also evident in their relatively safe outcomes during overdose attempts in adult populations. But prescribing trends were reversed as people in the medical community became more aware of the potential problems involving addiction and dependence associated with prolonged use of those agents. In addition, overdose mortality from anxiolytics and hypnotics/sedatives has risen dramatically [1],[2], and has involved in many presentations to the emergency departments as well as motor vehicle crashes [2],[3]. Those risks are more pronounced when benzodiazepines are combined with alcohol, opioids, or other medications that affect the central nervous system [2],[3].

Based on ethical considerations, children and adolescents are often excluded from clinical trials before the drug is marketed, and most use of anxiolytics and hypnotics/sedatives in this age group is an off-label prescription, meaning that the medication has not been tested and approved by the Food and Drug Administration of the United States of America for use in this age group. Therefore, close clinical monitoring of children receiving those drugs is warranted until clinical trials establish their safety and effectiveness in this population. Therefore, the trend of anxiolytic and hypnotic/sedative prescriptions is a pivotal indicator of patient safety for the population in children and adolescents.

The use of psychotropic medications among children and adolescents has increased markedly in the past two decades [4],[5],[6],[7],[8]. But the results of research are different on the trends of prescribing anxiolytics and hypnotics/sedatives among children and adolescents around the world. In the US, the study of Olfson et al. showed that a marked expansion exists in the use of psychotropic medications by children, especially stimulants and antidepressants. However, rates of benzodiazepines are increased only slightly, from 0.2 to 0.3/100 children [9]. As a global perception, psychotropic use in children and adolescents is increasing in the US. The prevalences of psychotropic drug prescription was 8.55% in 2004 and 9.00% in 2014. The prevalences for each drug class in 2004 and 2014 were stimulants/other ADHD drugs 5.0% and 5.8%, antidepressants 2.8% and 2.7%, anxiolytic/hypnotic-sedative 2.2% and 2.3%, respectively [10].

A similar trend was observed in the United Kingdom between 1992 and 2001. Increased prescribing was also noted for antidepressants (1.6-fold), hypnotics/anxiolytics (1.3-fold), antipsychotics (1.3-fold), and anticonvulsants (1.3-fold) throughout the study period [11]. In other European countries, the study of Zoëga et al. on pediatric psychotropic drug use in Iceland from 2003 to 2007 showed that increased prevalence has been observed for the use of stimulants, antipsychotics, anxiolytics and hypnotics/anxiolytics while the prevalence of antidepressant use is decreased. The proportion of participants received anxiolytics and hypnotics/anxiolytics has been increased during the study period (1.7‰ to 1.8‰ and 0.8‰ to 2.6‰, respectively) [12]. The study of Schirm et al. on pediatric psychotropic drug use in the Netherlands from 1995 to 1999, showed that the most widely used psychotropic agents among 0 to 19 years of age were stimulants (prevalence being 7.4/1,000 in 1999), followed by hypnotics/anxiolytics (6.9/1,000) [13].

In the past, anxiolytics and hypnotics/sedatives have been used in children and adolescents with anxiety disorders, sleep-related disorders, psychosis and aggression. In addition, psychiatrists also used anxiolytics for treating psychosis, autism, aggression, panic disorder, and impulse-control disorder not elsewhere classified [14]. But currently, no firmly established indication exists for the use of those medications in children or adolescents with psychiatric illnesses. In the past, the antipsychotic prescription pattern among child and adolescent patients with psychiatric illnesses in Taiwan has been discussed [15], few studies have reported data on the use of anxiolytics and hypnotics/sedatives in children and adolescents, and published studies on the characteristics and the trend of anxiolytics and hypnotics/sedatives use are lacking in Taiwan for the child and adolescent population with psychiatric illnesses. In this study, we intended to study the characteristics and the trend of the use of anxiolytics and hypnotics/sedatives in children and adolescent patients with psychiatric illnesses, and also to examine the associated factors for the prescription trend.


  Methods Top


Study design

This is a retrospective study for all outpatients who were equal or younger than 18 years of age. We collected related study variables from the electronic medical information system from 2006 to 2015 at Taoyuan Psychiatric Center (TYPC), where an electronic medical information system has been established since January 2000. The diagnostic system in Taiwan before 2016 was the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM). Therefore, we used ICD-9-CM diagnosis code to collect the information of patients' clinical diagnosis.

Study sample

This study was conducted at TYPC, a public, regional teaching hospital in the northern Taiwan, providing psychiatric service of 282 acute beds, 380 chronic beds, and 300 day-care beds, as well as active outpatient services including clinics for children and adolescents. The hospital is one of the biggest psychiatric services for children and adolescents in Taiwan.

TYPC provides various treatments for young psychiatric patients, including (a) outpatient treatment more than 2000 patient visits per month, (b) 100 day-care beds, and (c) 12 acute beds for children and adolescent patients. The study proposal was approved by the institutional review board of the TYPC (IRB protocol number = B20190624 and date of approval = September 4, 2018), without the stipulation to obtain the informed consents from the study patients.

Study instruments and variables as well as data extraction

Data from the electronic medical information system of the study hospital are transformed into a relational database, referred to as the data “warehouse.” We extracted study data from the warehouse and created our analytic data set with the Statistical Package for Social Science software version 20.0 for Windows (SPSS, Inc., Chicago, Illinois, USA) and Statistical Analytic System software version 9.3 (SAS Institute Inc., Cary, North Carolina, USA).

With reviewing the electronic medical information system, we extracted both patients' demographic data such as sex, age, insurance status, psychiatric diagnosis, and prescriptions of anxiolytics and hypnotics/sedatives. The insurance status was divided into patients with a catastrophic illness or without. The catastrophic illness in this study included chronic organic psychosis (ICD-9-CM: 294), schizophrenia (ICD-9-CM: 295), affective psychoses (ICD-9-CM: 296), paranoid states (ICD-9-CM: 297), and autism spectrum disorder (ICD-9-CM: 299). The patients with the status of a catastrophic illness do not need to pay any co-payment of medical expenses under the Taiwan National Health Insurance when they visit the clinics for the care for the stated catastrophic illnesses.

Anxiolytics and hypnotics/sedatives are classified using anatomical therapeutic chemical system of the World Health Organization (WHO), i.e., N05BA (anxiolytics – benzodiazepine derivatives), and hypnotics under N05CD (hypnotics and sedatives – benzodiazepine derivatives) and N05CF (hypnotics and sedatives – benzodiazepine-related drugs or Z-drugs). Clonazepam (N03AE01) was also included because it has anxiolytic properties, has been increasingly used in various psychiatric disorders [16],[17]. A study pharmacist (SW Cheng) with a more than 20-year experience in psychiatric research extracted the data. The corresponding author (HY Chan), a board-certificated psychiatrist, had regular supervisions and discussions on the extraction results.

Statistical analysis

Categorical variables were compared using Chi-square or Fisher's exact test, and continuous variables were compared using independent t-test. We did Cochrane-Armitage trend test to examine the time trend of prescribing anxiolytics and hypnotics/sedatives. Factors associated with the use of anxiolytics and hypnotics/sedatives were estimated using multiple logistic regression analysis. We included all of the covariates in the multivariable logistic regression model, including age, gender, status of catastrophic illnesses, and psychiatric diagnosis. All results were expressed as means ± standard deviations or numbers (percentages).

All statistical analysis in this study was done using Statistical Package for the Social Science software version 20.0 for Windows (SPSS, Inc., Chicago, Illinois, USA) and the Statistical Analytic System software version 9.3 (SAS institute Inc, Cary, North Carolina, USA). The differences between the groups were considered significant if p-values were smaller than 0.05.


  Results Top


There were 181,308 children and adolescent outpatient visits during the study period. The average age ± standard deviation of the study patients was 11.50 ± 3.81 years. A total of 13,065 visits had prescriptions for anxiolytics and hypnotics/sedatives, with the prescription rate of 7.21% (13,065/181,308), their average age ± SD was 15.29 ± 2.24 years, which was significantly higher than that of the patients without prescribed anxiolytics and hypnotics/sedatives (p < 0.001). The total average items of anxiolytics and hypnotics/sedatives prescriptions were 15,725 with 1.20 (15,725/13,065) items of anxiolytics and hypnotics/sedatives in each prescription. There were 2,426 children and adolescent outpatient visits with two or more anxiolytics and hypnotics/sedatives prescriptions at the same time with the percentage of anxiolytics and hypnotics/sedatives polypharmacy was 18.57% (2,426/13,065).

[Table 1] shows the comparison between anxiolytics and hypnotics/sedatives users and non-users among children and adolescent patients with psychiatric illnesses. The use of anxiolytics and hypnotics/sedatives drugs was significantly higher in the male patients than in the female patients, and was significantly increased with age after stratification by age (p < 0.001). Patients who received anxiolytics and hypnotics/sedatives had a significantly lower chance of having mental retardation diagnosis (p < 0.001), but a higher chance of having nonpsychotic disorders and autistic spectrum disorder diagnosis.
Table 1: Demographic data and baseline clinical characteristics of the study patients (n=181,308)

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[Table 2] shows the distribution of prescribing anxiolytics and hypnotics/sedatives in the study population. The proportions of anxiolytics and hypnotics/sedatives were 59.23% and 40.77%, respectively. In anxiolytics, clonazepam had the highest prescription rate (29.39%) and follows by lorazepam (20.72%). In hypnotics/sedatives, estazolam had the highest prescription rate (18.97%) and follows by zolpidem (8.38%).
Table 2: The distribution of prescriptions for anxiolytics and hypnotics/sedatives (n=15,725)

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[Table 3] shows the results of logistic regression for factors associated with anxiolytics and hypnotics/sedatives use. After adjusting for other variables, anxiolytics and hypnotics/sedatives prescription were significantly increased by 1.31 times (adjusted odds ratio [aOR] (1.31 [95% confidence interval (CI)] = 1.31 [1.30–1.33], p < 0.001)) every year with age, and by 1.34 times (aOR [95% CI] = 1.34 [1.28–1.40], p < 0.001) in the female patients compared to male patients. Furthermore, patients with catastrophic illnesses had significant higher risk of being prescribed with anxiolytics and hypnotics/sedatives (aOR [95% CI] = 1.45 [1.37–1.54], p < 0.001) than those without. After selecting autistic spectrum disorder as the reference group, patients with some diagnoses (affective psychosis [p < 0.001], schizophrenia [p < 0.001], neurotic disorders [p < 0.001], other psychotic disorders [p < 0.001], and paranoid states [p < 0.001]) all had significant higher chances of using anxiolytics and hypnotics/sedatives.
Table 3: Logistic regression for factors associated with anxiolytics and hypnotics/sedatives use

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[Table 4] shows the trend of anxiolytics and hypnotics/sedatives used from 2006 to 2015. The proportion of participants received anxiolytics and hypnotics/sedatives was decreased over the 10 years study period (from 9.16% to 5.85%, p < 0.001), anxiolytics were decreased non-significantly (from 5.34% to 4.54%, nonsignificance) but hypnotics/sedatives were decreased significantly (from 5.35% to 2.27%, p < 0.001) over the study period. The proportion of patients received anxiolytics and hypnotics/sedatives in different age group showed that the age group of below six years old demonstrates the highest decrease (from 0.63% to 0%, p < 0.001), and follows by age group of 10–12 years old (from 2.56% to 0.49%, p < 0.001). The proportion of patients received anxiolytics and hypnotics/sedatives showed a significant decrease trend over the study period in both genders (males from 6.44% to 4.71%%, p < 0.001; females from 17.12% to 9.33%, p < 0.001).
Table 4: The trend of anxiolytics and hypnotics/sedatives used from 2006 to 2015§

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  Discussion Top


To our best knowledge, this is the first study focusing on the prescriptions of anxiolytics and hypnotics/sedatives for psychiatric outpatients of children and adolescent patients in psychiatric services of Taiwan. In this study, we found that the proportion of prescribing anxiolytics and hypnotics/sedatives was decreased around 36.17% (from 9.16% in 2006 to 5.85% in 2015). We also found that the proportion of anxiolytics was nonsignificantly decreased, while hypnotics/sedatives were decreased significantly over the 10 years study period. The results of this study are valuable with important clinical implications in anxiolytics and hypnotics/sedatives prescriptions for children and adolescents.

Our study showed that the prevalence of declined prescriptions of anxiolytics and hypnotics/sedatives in the 10-year period and the result is different from those reports in some studies [7],[12],[13],[18],[19]. It may be due to that many physicians of Taiwan choosing antidepressants or second-generation antipsychotic drugs to replacing for hypnotics in recent years. Because antidepressant drugs and second-generation antipsychotics might be used as substitutes for benzodiazepines in some clinical conditions because of their anxiolytic or hypnotic effects [20],[21],[22]. In addition, the American Academy of Child and Adolescent Psychiatry (AACAP) published a position paper supporting the use of selective serotonin-reuptake inhibitors (SSRIs) as first-line pharmacotherapy for the treatment of depression among children and adolescents in 1998 [23]. Another issue is that some SSRIs and serotonin and norepinephrine-reuptake inhibitors have the indications for several anxiety disorders. They still have the advantage of lower dependency risk and less related side effects of anxiolytics and hypnotics/sedatives [24], several treatment guidelines suggest anxiolytics and hypnotics/sedatives can only be used in short-term and can choose antidepressants as the long-term medications for several psychiatric illnesses. These factors may contribute to decreased prescription of anxiolytics during the study period [22]. Nevertheless, the trends in the use of other psychotropic drugs were not analyzed in this study. We suggest that the mechanism by which the consumption of anxiolytics-hypnotics is affected by other psychotropic drugs warrants further studies.

Our study demonstrated that clonazepam was the highest prescription medication (29.39 % of all benzodiazepines) among anxiolytics [Table 2]. This study also showed that estazolam (18.97 % of all BZDs and BZD receptor agonists) and zolpidem (8.38% of all BZDs and BZD receptor agonists) are the most prescribed hypnotics for children and adolescent patients [Table 2]. The results are different from those published from some other studies. For adults, clonazepam is approved by the U.S. FDA for panic disorder, lorazepam for generalized anxiety disorder, and alprazolam for panic disorder as well as generalized anxiety disorder. Diazepam, chlordiazepoxide, and oxazepam have FDA-approved dosing for generalized anxiety disorder in children and adolescents [25]. As also noted as a similar phenomenon in Taiwan [26], clonazepam is widely used for various clinical indications, including insomnia, anxiety, convulsions, and even restless legs syndrome [27],[28],[29]. Moreover, it is possible that the study hospital is a specialized psychiatric center and most of the patients have severe or refractory mental illnesses. Therefore, the medication prescription pattern is different from the data of general hospitals or local clinics.

The gender and age are associated with the use of psychotropic medications among children and adolescents [30],[31],[32]. Our study results [Table 1] also showed significant differences existed in ages (p < 0.001), genders (p < 0.001), insurance status (p < 0.001), and psychiatric diagnoses (p < 0.001) among children and adolescents. In univariate analysis, our study [Table 1] showed that males had significantly higher proportion in receiving anxiolytics and hypnotics/sedatives than females (p < 0.001). The results of other studies were also found that males have higher chance to receive anxiolytics and hypnotics/sedatives in several countries [33]. But the multivariate logistic regression, our study [Table 3] showed that females have higher risk of receiving anxiolytics and hypnotics/sedatives than males. The result is in line with that of published previous studies [34],[35], reflecting on a higher prevalence of anxiety disorder, depression, and insomnia in children and adolescent female patients [7],[34]. This may be due to different study variable collection and adjustment in the regression model among different studies. Further studies are needed to ascertain whether gender is a risk factor in prescribing anxiolytics and hypnotics/sedatives.

Some previous studies were found that the prevalence of prescribing anxiolytics and hypnotics/sedatives in the children and adolescents, and the use of those classes of medications is positively correlated with increased ages [30],[36]. Our study [Table 4] showed that the use of those medications in the age group of under six years was significantly decreased in both genders (p < 0.001). In the age group of six years or older [Table 4], and the age of 10-12 years in the male (p < 0.001) and the age of 7-9 years in the female (p < 0.001) showed significantly the highest decreased use in the use of those medications. Our study result [Table 4] was also found that the prescription of anxiolytics was significantly associated with diagnosis (p < 0.001). Patients with mental retardation diagnosis had a significantly less chance of receiving anxiolytics and hypnotics/sedatives (p < 0.001). Mental retardation was a group of disorders defined by diminished cognitive and adaptive development, and there are at considerable risk for the development of comorbid psychiatric conditions, such as mood disorders, anxiety disorders, schizophrenia. Psychopharmacological treatments may have a crucial rôle in a multidisciplinary and multimodal approach in managing comorbid psychiatric conditions for this population. Benzodiazepines can be used as possible alternative treatment of anxiety disorders for mental retardation. But hostility, disinhibition, self-injurious behaviors, and aggression have been reported as paradoxical reactions to benzodiazepines, especially in people who exhibit evidence of stereotypical, self-injurious behaviors before starting treatment with benzodiazepines. Furthermore, long-term benzodiazepines use can result in increased risk of cognitive deficits. In addition, benzodiazepines have an increased risk for abuse, tolerance, and dependence. Therefore, the clinical consensus advises that benzodiazepines alone should only be used for a maximum of three weeks [37]. In addition, several studies have been reported that buspirone improves agitation and behavioral problems, including aggression and self-injury, in people with developmental disabilities [38]. These factors may have contributed to decreasing anxiolytics prescription during the study period.

Our study [Table 4] also showed that schizophrenia (p < 0.001), other psychotic disorders and paranoid state (p < 0.001), had a significant higher chance of receiving anxiolytics and hypnotics/sedatives. They are mainly used to relieve anxiety and sleep problems induced by these diseases among children and adolescents. Benzodiazepines can be taken alone or in combination with antipsychotic drugs to cause sedation, calmness and relax the muscles, so are helpful in calming down agitated patients and patients with acute mental health problems [39].

Our study [Table 4] also showed that patients with catastrophic illnesses had a significant higher chance of being prescribed with anxiolytics and hypnotics/sedatives (aOR [95% CI] = 1.45 [1.37–1.54], p < 0.001) than those without. In general condition, patients with catastrophic illnesses have more severe psychiatric symptoms and more psychiatric comorbidity than those without. Under such circumstances, the chances for those patients to receive anxiolytics and hypnotics/sedatives would be higher than patients without to relieve insomnia, anxiety or even agitated symptoms. Further studies are also needed to confirm whether catastrophic illness is a risk factor in using anxiolytics and hypnotics/sedatives.

Study limitation

The readers are warned not to over-interpreting the study results because this study has four limitations:

  • We included the data of patients of only one single psychiatric center. The findings from this study may not be generalized to other studies because of differences in local practice patterns.
  • The psychiatric diagnoses from the electronic database might be incorrect in some patients and different from those in real clinical circumstances.
  • Some variables are related to anxiolytics and hypnotics/sedatives treatment for children and adolescent studies, but are difficult to retrieve from a retrospective study. Those data include the profiles and severity of psychotic/mood/anxiety symptoms, family support, doctors' and patients' attitude toward a specific medication, previous history and treatment responses of psychotropic medications, and the policy changes of the Bureau of National Health Insurance of Taiwan during the study period. To further investigate probable mechanisms explaining the proportion and trend changes over the study period was difficult in this study.
  • Patients' laboratory data were not available in this study. Therefore, we did not know the effects of anxiolytics and hypnotics/sedatives on the cognitive function and other related profiles which need the data of laboratory examinations.


Summary

Our study showed that the proportion of prescribing anxiolytics and hypnotics/sedatives was decreased around 36.17% (from 9.16% to 5.85%), and the most important contributors for prescription decrease over the study period was the age group of 1 - 6 years in anxiolytics prescription. The results are in line with the recommendation of most guidelines in decreasing anxiolytics and hypnotics/sedatives use for psychiatric patients below 18 years of age.

Certainly, we need more well-designed clinical studies to investigate the safety and efficacy of those anxiolytics and hypnotics/sedatives for children and adolescents. To study how and why these medications are being prescribed is necessary, using the application of pharmacoepidemiology. We believe the use of anxiolytics and hypnotics/sedatives in children and adolescents is a global public health issue, which should be studied in partnership with experts in pharmaceutical companies, governments, and researchers to expand the evidence for their use in children and adolescents.


  Acknowledgment Top


Both authors, Shu-Wen Cheng and Hsiao-Ju Sun, contributed equally as two first authors of this article. The funding body played no rôle in the study design, analysis, or interpretation of the study data in this paper.


  Financial Support and Sponsorship Top


This study was supported by a grant from the Taoyuan Psychiatric Center, Ministry of Health and Welfare of Taiwan (TYPC-10901).


  Conflicts of Interest Top


All authors declare no conflicts of interest in writing this paper.



 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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