Association between serum testosterone levels and the severity of negative symptoms in male patients with chronic schizophrenia

ARTICLE IN PRESS Psychoneuroendocrinology (2007) 32, 385–391

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Association between serum testosterone levels and the severity of negative symptoms in male patients with chronic schizophrenia Young-Hoon Koa, Sung-Won Jungb, Sook-Haeng Joec,, Chang-Hyun Leeb, Hyun-Gang Jungc, In-Kwa Jungc, Seung-Hyun Kimc, Moon-Su Leec a

Department of Psychiatry, Korea University College of Medicine, Ansan Hospital, Gojan-1(il)-dong, Danwon-gu, Ansan-si, Gyeonggi-do 425-707, Korea b Department of Psychiatry, Bugok National Hospital, Bugok-myeon, Bugok-ri, Changnyeong-gun, Gyeongsangnam-do 635-893, Korea c Department of Psychiatry, Korea University College of Medicine, Guro Hospital, #97 Gurodong-gil, Guro-2-dong, Guro-gu, Seoul 152-703, Korea Received 10 July 2006; received in revised form 18 January 2007; accepted 1 February 2007

KEYWORDS Schizophrenia; Negative symptoms; Testosterone; Free testosterone

Summary Objectives: Dysfunction of the hypothalamic–pituitary–gonadal axis may contribute to the pathophysiology of schizophrenia. Recent neuroendocrinological studies have suggested that gonadal sex hormones, including androgens and estrogen, play a significant role in the pathophysiology of schizophrenia. The purpose of this study was to determine any correlation between negative symptoms and the plasma levels of free testosterone, total testosterone, dehydroepiandrosterone sulfate, estradiol, and prolactin with consideration to depressive symptoms, extrapyramidal symptoms (EPS), and other factors including differences in age, diurnal variation of the serum hormone levels, and body fat composition. Methods: The subjects were 35 male inpatients with chronic schizophrenia aged 20–39 years. The patients’ psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). The Calgary Depression Scale for Schizophrenia (CDSS) and the Drug-induced EPS scale (DIEPSS) were also used to exclude the effects of depression or drug-induced movement disorders. Results: The PANSS negative scores had a significant inverse correlation with the serum total and free testosterone levels. The other hormone levels were not correlated with the PANSS negative scores. Moreover, a partial correlation analysis showed an inverse

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E-mail addresses: [email protected], , [email protected] (S.-H. Joe). 0306-4530/$ - see front matter & 2007 Published by Elsevier Ltd. doi:10.1016/j.psyneuen.2007.02.002

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Y.-H. Ko et al. correlation between the PANSS negative subscores and the serum total and free testosterone levels after controlling for the DIEPSS and/or CDSS scores and age. Conclusions: This study indicates that total and free testosterone may play an important role in the severity of negative symptoms in male patients with schizophrenia. & 2007 Published by Elsevier Ltd.

1. Introduction The onset of the symptoms of schizophrenia that usually occurs around adolescence suggests a relationship between this disorder and reproductive hormones. Neuroendocrinological studies have suggested that dysfunction of the hypothalamic–pituitary–adrenal and/or hypothalamic–pituitary–gonadotropin axis may contribute to the pathophysiology of schizophrenia. In the past decade, there have been several reports supporting a relationship between estrogen and the psychopathology of schizophrenia, and these studies suggested a neuroprotective effect of estrogen. While recent animal research has indicated that androgens may regulate the actions of various neurotransmitters and neuropeptides (McEwen, 1991), there have been fewer studies investigating the relationship of androgens with schizophrenia, and these studies have shown inconsistent findings. Previous studies that have evaluated the relationship between the serum levels of testosterone and schizophrenia have not shown consistent results (Rinieris et al., 1989; Kaneda and Fujii, 2000; Kaneda, 2001; Taherianfard and Shariaty, 2004). Other studies investigating the relation of dehydroepiandrosterone (DHEA) and/or its sulfate conjugate (DHEAS) (together abbreviated DHEA(S)) with schizophrenia have also shown diverse findings (Brophy et al., 1983; Oades and Schepker, 1994; Harris et al., 2001; Ritsner et al., 2004, 2005; Strous et al., 2004). However, with respect to the psychopathology of schizophrenia, limited recent studies have shown that there might be a consistent relationship between the serum levels of androgen, especially the level of testosterone, and negative symptoms in male patients with schizophrenia (Shirayama et al., 2002; Goyal et al., 2004; Akhondzadeh et al., 2006). The negative symptoms of schizophrenia include affective flattening, alogia, avolition, anhedonia, and impaired attention (Andreasen, 1982). However, some authors have suggested that drug-induced extrapyramidal symptoms (EPS) (Van Putten, 1974; Prosser et al., 1987) and depressive symptoms (Prosser et al., 1987) occurring in the course of this illness may confound the negative symptoms. Therefore, because these symptoms may be shared or combined, clinicians and researchers have had difficulty differentiating between them because of overlapping clinical criteria. Moreover, some studies on the relationship between testosterone levels and depression have demonstrated that testosterone levels are related to depressive illness (Sternbach, 1998; Seidman and Walsh, 1999), including the depressive episodes that occur in male schizophrenic patients (Kaneda, 2003). However, there is a paucity of studies investigating the relationship of negative symptoms

with androgens in male schizophrenia patients considering the interactions between negative, depressive, and EPS. The aim of this study was to identify the relationship between the severity of negative symptoms and the serum of total and free testosterone and DHEAS levels in male patients with chronic schizophrenia, and to consider various confounding factors. In addition, we measured the serum levels of prolactin and estradiol to gather additional information about the involvement of these reproductive hormones in the negative symptoms.

2. Methods 2.1. Subjects Thirty-five male inpatients aged 20–39 years who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia participated in this study. The diagnosis was based on semistructured clinical interviews and reviews of medical records. Informed consent was obtained from all patients or their guardians after the procedures of the study had been fully explained to them. The patients were enrolled from several psychiatric wards at the National Bugok Hospital in Korea. They all had chronic schizophrenia, defined as having suffered from schizophrenia symptoms for at least 2 years before recruitment (Chatterjee et al., 2003). Their psychiatric symptoms were stable before the examination, and their doses of antipsychotic medications and other concomitant psychotropic medications such as benzodiazepines, antiparkinsonian agents, mood stabilizers, and/or hypnotics were fixed for at least 2 weeks before participation in this study. The patients were considered symptomatically stable if there had been no appreciable change in their psychotic symptoms during the 4 weeks before participation in this study, regardless of the severity of their symptoms. All the subjects were smokers and they had no abnormal findings as evidenced by medical histories, physical examinations, complete blood counts, urinalysis, and serum biochemistry. They also had no other chronic medical illness, substance abuse (including anabolic steroids), or substance dependence in the past year. Subjects with a body mass index (BMI) less than 20 kg/m2 or more than 30 kg/m2 were excluded.

2.2. Measures On the morning of the day when blood samples were drawn for estimation of the hormone levels, each subject received psychopathology assessment using the Positive and Negative

ARTICLE IN PRESS Serum testosterone and negative symptoms in male schizophrenia Symptoms Scale (PANSS) (Kay et al., 1987). To evaluate the patients’ EPS and depressive mood, the drug-induced EPS scale (DIEPSS) (Inada, 1996) and the Calgary Depression Scale for Schizophrenia (CDSS) (Addington et al., 1990) were used, respectively.

2.3. Hormone assays Between 8:30 AM and 9:30 AM, 10 ml of blood was collected into a tube containing 2% heparin. The total and free serum testosterone, estradiol, DHEAS, and prolactin levels were measured for each patient by the same laboratory. The methods used for the measurement were chemiluminescent immunoassays (Bayer, USA) for the total testosterone, estradiol, and prolactin; an immunoradiometric assay (Diagnostic Products, USA) for free testosterone; and a radioimmunoassay (Diagnostic Products, USA) for DHEAS. The serum samples were assayed in batches in the same assay to avoid any possible bias produced by inter-assay variation. The intra-assay coefficients were below 10% for all assays. The sensitivities of the assays were total testosterone, 0.35 ng/ml; free testosterone, 0.15 pg/ml; DHEAS, 1.1 mg/dl; estradiol, 10 pg/ml; and prolactin, 0.3 ng/ ml. The reference ranges used were total testosterone, 2.41–8.27 ng/ml; free testosterone, 8.8–27.0 pg/ml; DHEAS, 80–560 mg/dl; estradiol, 11.6–41.2 pg/ml; and prolactin, 2.1–17.7 ng/ml.

2.4. Statistical analysis The descriptive statistics for each of the variables were calculated. Before analysis, each variable was examined for its distributional characteristics. All the data in the figures and tables are shown as means (7SD). The relationships between the serum hormone levels and the PANSS negative scores were analyzed by Pearson’s correlation analysis; if there was a significant correlation, it was further analyzed by a partial correlation analysis after controlling for the scores on the DIEPSS and/or CDSS and age. For the categorical variables, bivariate analyses were conducted with Spearman’s rho correlation. The Bonferroni correction was used to adjust for multiple comparisons. All the statistical tests were evaluated at the 5% significance level (two-tailed). SPSS version 10.0 (SPSS, USA) was used for all analyses.

3. Results The mean age of the patients was 33.673.6 years (range, 25–39 years), and the mean duration of illness was 10.976.1 years. The patients were taking antipsychotics with daily dosages ranging from 100 to 900 mg of chlorpromazine equivalents during the 9.876.4 weeks before the study and at the time of their examinations (Table 1). Of the 35 subjects, 18 (51.4%) were receiving risperidone, six (17.1%) clozapine, three (8.6%) chlorpromazine, three zotepine, two (5.7%) amisulpride, one (2.9%) olanzapine, one (2.9%) aripiprazole, and one (2.9%) quetiapine. The prescribed antipsychotics were grouped into the prolactin-raising antipsychotics and the prolactin-sparing antipsychotics to identify their association with the serum hormone levels. Risperidone, chlorpromazine, and amisulpride are the

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Table 1 Demographic data and baseline characteristics of male patients with chronic schizophrenia. Age (years) Education duration (years) Number of relapses Length of illness (years) Body mass index (kg/m2) Daily dose of antipsychotic drugs (mg, chlorpromazine equivalent) Length of maintenance treatment with current antipsychotic drugs (weeks)

33.673.6 12.572.2 7.375.2 10.976.2 23.272.6 339.47166.8 9.776.6

Current antipsychotic drugs Risperidone Clozapine Chlorpromazine Zotepine Amisulpride Olanzapine Aripiprazole Quetiapine

18 (51.4%) 6 (17.1%) 3 (8.6%) 3 (8.6%) 2 (5.7%) 1 (2.9%) 1 (2.9%) 1 (2.9%)

Serum hormone level Total testosterone (ng/ml) Free testosterone (pg/ml) DHEAS (mg/dl) Estradiol (ng/ml) Prolactin (ng/ml)

3.7371.47 7.6072.65 195.87107.3 15.3376.45 29.57722.55

PANSS Total Positive Negative General

71.5717.8 17.074.2 19.876.1 34.779.8

DIEPSS CDSS

1.171.4 4.273.6

PANSS, positive and negative syndrome scale; DIEPSS, druginduced extrapyramidal symptoms scale; CDSS, Calgary Depression Scale for Schizophrenia.

prolactin-raising agents, and the others are the prolactinsparing agents (Wieck and Haddad, 2003; El-Sayeh et al., 2006). However, the prolactin-raising property did not show any significant relationship with any of the hormone levels except for the prolactin levels (r ¼ 0.615, Po0.001). Other measures related to the antipsychotic medication, including the duration and the dosage of current antipsychotic medications, had no relationship with the serum hormone levels. The mean serum levels of total testosterone, free testosterone, DHEAS, estradiol, and prolactin were 3.7371.47 ng/ml, 7.6072.65 pg/ml, 195.87107.3 mg/dl, 15.3376.45 ng/ml, and 29.57722.55 ng/ml, respectively (Table 1). Table 2 demonstrates the correlation coefficients (r) for the serum hormone levels of the patients after Bonferroni correction for multiple comparisons (Po0.005). The total testosterone levels showed a significant correlation with the

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Y.-H. Ko et al.

Table 2 Correlations between serum levels of total testosterone, free testosterone, DHEAS, estradiol, and prolactin in male patients with chronic schizophrenia. r Total testosterone Total testosterone Total testosterone Total testosterone Free testosterone Free testosterone Free testosterone DHEAS DHEAS Estradiol

P

Free testosterone 0.72 o0.001 DHEAS 0.42 0.012 Estradiol 0.20 0.24 Prolactin 0.15 0.40 DHEAS 0.003 0.98 Estradiol 0.438 0.008 Prolactin 0.124 0.48 Estradiol 0.02 0.93 Prolactin 0.20 0.24 Prolactin 0.19 0.28

Analyzed by Pearson correlation, level of significance after Bonferroni correction for multiple comparison was adjusted to Po0.005.

free testosterone levels (r ¼ 0.72, Po0.001), and the free testosterone levels had an insignificant trend correlation with the estradiol levels (r ¼ 0.438, P ¼ 0.008). No other significant correlations among the hormone levels were shown. The PANSS negative scores had a significant inverse correlation with the serum total and free testosterone levels (r ¼ 0.50, P ¼ 0.002; r ¼ 0.48, P ¼ 0.003, respectively) after Bonferroni correction for multiple comparisons (Po0.01). The other hormone levels were not correlated with the PANSS negative scores (Fig. 1). Moreover, a partial correlation analysis showed an inverse correlation between the PANSS negative subscores and the serum total and free testosterone levels after controlling for the DIEPSS and/or CDSS scores and age (Table 3).

4. Discussion The results of this study indicate that the serum testosterone level is inversely correlated with negative symptoms in male patients with chronic schizophrenia. This correlation

Figure 1 The correlation between serum levels of total testosterone and free testosterone and scores on PANSS negative subscale (r ¼ 0.50, P ¼ 0.002; r ¼ 0.48, P ¼ 0.003, respectively). The level of significance after Bonferroni correction for multiple comparisons was adjusted to Po0.01. PANSS: Positive and Negative Syndrome Scale.

Table 3 Partial correlations between serum hormone levels and scores on PANSS negative subscale after controlling for scores on DIEPSS and/or CDSS and age. Covariate

DIEPSS and age CDSS and age DIEPSS, CDSS, and age

Total testosterone

Free testosterone

DHEAS

Estradiol

Prolactin

r

P

r

P

r

P

r

P

r

P

–0.50 –0.49 –0.49

0.002 0.004 0.004

–0.47 –0.46 –0.46

0.005 0.006 0.006

0.09 0.09 0.09

0.62 0.62 0.62

–0.09 –0.10 –0.09

0.59 0.60 0.61

0.02 0.02 0.07

0.93 0.93 0.71

PANSS, positive and negative syndrome scale; DIEPSS, drug-induced extrapyramidal symptoms scale; CDSS, Calgary Depression Scale for Schizophrenia. The level of significance after Bonferroni correction for multiple comparison was adjusted to Po0.01.

ARTICLE IN PRESS Serum testosterone and negative symptoms in male schizophrenia remained nearly unchanged even after controlling statistically for EPS and depression. However, with respect to the serum DHEAS and estradiol levels, we could not find any association with the negative symptoms in the patients. These findings suggest that lower total and free testosterone levels may reflect more severe negative symptoms in male patients with schizophrenia. This is consistent with previous studies, even though the studies are somewhat different. Previous studies have tried to determine the relationship between androgens and schizophrenia in male patients. Several studies have demonstrated significantly lower testosterone levels in patients treated with high dose typical antipsychotics (Rinieris et al., 1989; Kaneda and Fujii, 2000; Kaneda, 2001). In male patients with schizophrenia, the serum testosterone levels were significantly lower before and during treatment, but not after recovery, compared with healthy subjects (Taherianfard and Shariaty, 2004). However, another study reported that male inpatients with schizophrenia had higher serum testosterone levels when compared with patients with mood disorders (Mason et al., 1988, 1991). With respect to DHEA and its sulfate conjugate DHEAS, one study demonstrated low DHEA levels in schizophrenic patients compared with healthy controls (Harris et al., 2001); however, other studies did not show any differences between patients with schizophrenia and normal controls (Brophy et al., 1983; Ritsner et al., 2004, 2005). Another study showed higher DHEAS levels in young male patients with schizophrenia (Oades and Schepker, 1994) and higher DHEA(S) levels in first-episode schizophrenia subjects (Strous et al., 2004). The aforementioned studies investigating the serum androgen levels as a disease-specific marker in male schizophrenics showed inconsistent findings, yet recent studies have consistently indicated that negative symptoms may have a negative correlation with serum androgen levels. Shirayama et al. (2002) reported a significant negative correlation of negative symptoms with plasma levels of testosterone, but not with DHEAS levels, in male patients with schizophrenia. However, Goyal et al. (2004) demonstrated that both serum testosterone and DHEAS levels were lower in a patient group with predominantly negative symptoms than in a patient group with predominantly positive symptoms. Another recent study reported that negative symptoms had a negative correlation with serum testosterone and free testosterone levels in schizophrenic patients with predominantly negative symptoms (Akhondzadeh et al., 2006). However, these studies did not consider various confounding factors such as depression and EPS, which may influence either negative symptoms or the serum testosterone levels in schizophrenia. It is well known that there is a problem in conceptual or methodological approaches to the overlap between negative symptoms, depressive symptoms, and EPS in schizophrenia. Prosser et al. (1987) suggested clinical difficulties in discriminating between negative symptoms and certain parkinsonian features such as a lack of facial expression, bradykinesia, and tremor. In addition, Dollfus et al. (2000) pointed out that objectively assessed EPS were strongly correlated with negative symptoms while subjectively assessed EPS were not. In addition, it is difficult to distinguish depressive symptoms, especially akinesia, from negative symptoms and EPS because the assessment criteria

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for depression overlap those for negative symptoms and EPS (Carpenter et al., 1985; Prosser et al., 1987; de Leon et al., 1989). Moreover, in patients with schizophrenia, it has been reported that testosterone may contribute to the pathophysiology of depressive symptoms (Kaneda, 2003) and EPS, especially parkinsonian symptoms (Harris et al., 2001). Therefore, any research results pertaining to negative symptoms should be interpreted with considerable caution (Sommers, 1985). To investigate the relationship between negative symptoms and androgens, the interaction between negative symptoms, depression, and EPS should also be considered. By excluding the effects of interactions between these symptoms, this study corroborates earlier findings on the relationship between testosterone and the symptomatology of schizophrenia in male patients. Testosterone is largely bound to plasma proteins, with only 1–2% being free testosterone (Dunn et al., 1981). This diffuses into target cells where it binds to the specific androgen receptor (Giorgi and Stein, 1981). Estrogen is produced by aromatization of testosterone (Gooren and Toorians, 2003) and acts via the estrogen receptor to mediate the effects of androgens in the brain (McEwen and Alves, 1999). The results of this study indicate that the serum levels of free testosterone are positively correlated with the serum levels of total testosterone and estradiol. These results confirm the previous finding of metabolic interactions between total and free testosterone and estrogen. Although there are a few studies regarding the relationship of testosterone with negative symptoms of schizophrenia, several previous studies offer possible explanations for the psychobiological role of testosterone in the negative symptoms of schizophrenia. The receptors of gonadal hormones are concentrated in hypothalamic and limbic systems involved in perception, cognition, and behavior (Steven, 2002). In the brain, as mentioned above, testosterone’s action may be mediated directly via the androgen receptor or indirectly via the estrogen receptor. Testosterone in its free form crosses the blood–brain barrier and then modulates the action of various neurotransmitters and neuropeptides through nongenomic or genomic mechanisms (Bialek et al., 1997). There is evidence suggesting that the limited availability of neurotransmitters such as dopamine, serotonin, and norepinephrine, along with dysregulation of the glutaminergic system, might form the pathophysiological basis for the negative symptoms of schizophrenia (Rau and Ko ¨lsch, 2003). Thus, the biochemical activity of testosterone may contribute to the negative symptomatology of schizophrenia. Pathophysiological processes involved in neurodegeneration may also be implicated in deteriorating forms of schizophrenia (Lieberman et al., 1997). There is evidence supporting the neuroprotective effect of testosterone in some neurodegenerative diseases, including Alzheimer’s disease, mild cognitive dysfunction, and depression. In addition, experimental studies have shown that testosterone exerts neuroprotective or neurotrophic actions on motor and autonomic neurons (Bialek et al., 1997). These findings also suggest a potent mechanism by which testosterone can affect the negative symptoms of schizophrenia via neuroprotection. There are many factors affecting serum androgen levels in men and in male schizophrenics. First, serum testosterone

ARTICLE IN PRESS 390 levels decline with age, starting to decline in the fifth decade of life (Gray et al., 1991). Maximal values of circulating DHEAS are reached between the ages of 20 and 30 years (Orentreich et al., 1984; Labrie et al., 1997). In young men, the serum testosterone level has diurnal variation, with the highest values at 8 AM and the lowest values in the late afternoon (Bremner et al., 1983). Therefore, to reduce the aging effect on androgen levels, we recruited young male schizophrenic patients aged between 20 and 39 years old, and clarify the results by partial correlation after controlling for age. In addition, to exclude the bias of diurnal variation, blood sampling was conducted between 8 and 9 AM. Second, adiposity, as assessed by the BMI, is a negative determinant of serum testosterone levels (Zumoff et al., 1990). Schizophrenia patients commonly suffer weight gain, and the estimated prevalence of obesity in this population is threefold that of the general population (Coodin, 2001). An unhealthy diet and lifestyle, the negative syndrome, and the direct effects of antipsychotic medication may predispose schizophrenics to weight gain (Allison et al., 1999; Brown et al., 1999). Previous studies did not consider the effect of obesity on the serum testosterone levels; however, we excluded subjects with obesity, as defined as a BMI of over 30 kg/m2. Although they are somewhat different, both the conventional and atypical antipsychotic agents not only contribute to weight gain but they also raise the serum prolactin level. The main limitation of the present study is that all the subjects had received antipsychotic medication and other psychotropic medications. The mean serum levels of prolactin were relatively high at 29.57722.55 ng/ml. Antipsychotic medication-induced hyperprolactinemia primarily suppresses the pulsatile secretion of gonadotropin-releasing hormone by the hypothalamus (Molitch, 2001), and this enhances hypogonadotropic hypogonadism. A previous study demonstrated that low testosterone levels and high prolactin levels were found in male schizophrenic patients with predominantly negative symptoms, and the prolactin level was positively correlated with the severity of the negative symptoms (Melkersson et al., 2001). However, in our study, the serum prolactin levels did not show any significant correlation with the other hormone levels or the severity of negative symptoms. Finally, it has been reported that stress (Christiansen et al., 1985), diet (Deslypere and Vermeulen, 1984), exercise (Zmuda et al., 1996), and sexual activity (Jannini et al., 1999) have an influence on serum testosterone levels. It was possible that these factors are involved in determining the serum testosterone levels in each patient in this study. There were several limitations of this study. We did not measure other related hormone levels, including the gonadotropin-releasing hormone, luteinizing hormone, adrenocorticotropic hormone, cortisol, and DHEA levels, and thus we did not identify their associations with testosterone, DHEAS, estradiol levels, and negative symptoms in our patient group. In addition, the sample size was small and the hormone levels were measured at a single point in time. Nevertheless, this study indicated that serum levels of testosterone might be associated with the severity of the negative symptoms after controlling for various confounding factors, especially depressive symptoms and EPS. It is suggested that total and free testosterone may

Y.-H. Ko et al. play an important role in the symptomatology of male patients with schizophrenia. In the future, further research that investigates an associative relationship of testosterone with negative symptoms would be helpful to plan a strategy to treat male schizophrenia patients with predominantly negative symptoms.

Role of the funding source This research was supported in part by a Korea University Grant to YHK and by Hanmi Pharmaceutical Ind. Co., Seoul, Korea; The Korea University and Hanmi Pharmaceutical Ind. Co. had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest All authors declare that they have no conflicts of interest.

Acknowledgements Some of these results were presented in October 2005, at the 18th European College of Neuropsychopharmacology Congress, Amsterdam, Netherlands. The authors gratefully acknowledge the support of the physician and staff of Bugok National Hospital who facilitated the implementation of this research.

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