Effect of olanzapine orally disintegrating tablet versus oral standard tablet on body weight in patients with schizophrenia: a randomized open-label trial

Progress in Neuro-Psychopharmacology & Biological Psychiatry 36 (2012) 313–317

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Effect of olanzapine orally disintegrating tablet versus oral standard tablet on body weight in patients with schizophrenia: a randomized open-label trial Ichiro Kusumi a,⁎, Minoru Honda b, Keiichi Uemura c, Yasuhumi Sugawara d, Masako Kohsaka e, Akihiko Tochigi f, Tsukasa Koyama a a

Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan Honda Memorial Hospital, Eniwa, Japan Department of Psychiatry, Sapporo City General Hospital, Sapporo, Japan d San-ai Hospital, Noboribetsu, Japan e Ishikane Hospital, Sapporo, Japan f Midorigaoka Hospital, Tomakomai, Japan b c

a r t i c l e

i n f o

Article history: Received 26 September 2011 Received in revised form 9 November 2011 Accepted 10 November 2011 Available online 15 November 2011 Keywords: Olanzapine Oral standard tablet Orally disintegrating tablet Schizophrenia Weight gain

a b s t r a c t Olanzapine has frequently been reported to induce substantial weight gain, which is associated with an increased prevalence of dyslipidemia and type 2 diabetes. Several reports have described that olanzapine orally disintegrating tablets (ODT) induce less weight gain than oral standard tablets (OST) do, although both forms have equal bioavailability. We tried to clarify whether or not body weight change differed between olanzapine ODT and OST treatments in olanzapine-naïve schizophrenia patients. An open-label, 12-month, multicenter, randomized, flexible-dose study was conducted for direct comparison of the effects of OST (mean dosage, 15.7 mg; N = 57) and ODT (mean dosage, 15.2 mg; N = 61) on body weight and metabolic measures such as blood glucose, hemoglobinA1c, total cholesterol and HDL-cholesterol, and triglycerides in olanzapinenaïve patients with schizophrenia. Outcome measures included Positive and Negative Syndrome Scale (PANSS), Global Assessment of Function (GAF), The World Health Organization Quality of Life 26 (WHOQOL26), Drug Attitude Inventory (DAI)-10, and tolerability assessed by the UKU side-effect rating scale. This study was conducted between June 2007 and April 2010. No significant difference was found in the weight gain between the two forms of olanzapine. No significant difference was found between the two groups in any metabolic measure, efficacy, tolerability, WHO-QOL26, or DAI-10 score. Previous reports describing that olanzapine ODT induced less weight gain than OST were not supported by results of this randomized study. © 2011 Elsevier Inc. All rights reserved.

1. Introduction Atypical antipsychotics, which can induce substantial weight gain, have been associated with increased prevalence of dyslipidemia and diabetes mellitus (Graham et al., 2008; Newcomer, 2004), which are risk factors for cardiovascular diseases (Bobes et al., 2007; Daumit et al., 2008). Clozapine and olanzapine appear to carry a greater potential than other atypical antipsychotics to induce weight gain and metabolic disturbances (American Diabetes Association et al., 2004).

Abbreviations: OST, oral standard tablet; ODT, orally disintegrating tablet; Cmax, maximum concentration; Tmax, time of maximum concentration; AUC, area under the curve; HbA1c, hemoglobinA1c; HDL, high-density lipoprotein; PANSS, Positive and Negative Syndrome Scale; GAF, Global Assessment of Function; WHO-QOL26, World Health Organization Quality of Life 26; DAI, Drug Attitude Inventory; ANOVA, analysis of variance. ⁎ Corresponding author at: Department of Psychiatry, Hokkaido University Graduate School of Medicine, North 15, West 7, Kita-ku, Sapporo 060–8638, Japan. Tel.: + 81 11 706 5160; fax: + 81 11 706 5081. E-mail address: [email protected] (I. Kusumi). 0278-5846/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2011.11.004

Olanzapine formulations of two types are available for clinical use: oral standard tablets (OST) and orally disintegrating tablets (ODT). There have been several reports examining the difference in effects of olanzapine OST and ODT on weight gain (Table 1). Some reports have described less weight gain or weight loss in schizophrenia patients switching from olanzapine OST to ODT therapy (Chawla and Luxton-Andrew, 2008; De Haan et al., 2004). Two non-randomized open-label studies have shown that olanzapine ODT induced less weight gain than OST in first-episode psychotic patients for 6 weeks (Arranz et al., 2007) and in adolescent patients with schizophreniform disorder for 12 weeks (Crocq et al., 2007). Although bioequivalence was established using measures of maximum concentration (Cmax), the time of maximum concentration (Tmax) and the area under the curve (AUC), results of a pharmacokinetic study suggest that olanzapine ODT administration caused an earlier detectable concentration relative to OST (Markowitz et al., 2006). The mechanism for the potential difference in weight gain between the two formulations has not been elucidated, although several hypotheses have been proposed (Karagianis et al., 2008). Recently, a 16-week, randomized,

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Table 1 The effects of olanzapine ODT and OST on body weight. Authors

Number

Subject

Study design

Duration

Dosage

Weight change

De Haan et al. (2004)

18 (17 M; 1 F) 52 (26 M;26 F)

recent-onset schizophrenia treated with OST adolescent schizophniform disorder

non-randomized open non-randomized open

16 W

38 (27 M;11 F) 22 (14 M;8 F) 149 (81 M;68 F)

first-episode, never-treated psychotic patients schizophrenia treated with OST schizophrenia, schizoaffective disorder, psychotic disorder, bipolar disorder previously gained weight with OST

non-randomized open switch from OST to ODT, open randomized double-blind double-dummy

10.4 mg (OST) 12.5 mg (ODT) 18.0 mg (OST) 16.6 mg (ODT) 2.8 mg (RIS) 13.8 mg (OST) 15.8 mg (ODT) 13.9 mg (ODT)

+ 6.6 kg (OST) − 3.6 kg (ODT) + 8.9 kg (OST) + 3.0 kg (ODT) + 1.0 kg (RIS) + 6.3 kg (OST) + 3.3 kg (ODT) − 2.7 kg (ODT)

14.9 mg (OST) 14.3 mg (ODT)

+ 2.08 kg (OST) + 1.42 kg (ODT) N.S.

Crocq et al. (2007)

Arranz et al. (2007) Chawla & LuxtonAndrew (2008) Karagianis et al. (2009)

12 W

6W 12 M 16 W

M: male, F: female W: week, M: month N.S.: not significant. OST: olanzapine oral standard tablet, ODT: olanzapine oral disintegrating tablet.

double-blind report described no significant difference in weight change between olanzapine OST and ODT in patients who had already gained weight during olanzapine OST treatment before entry (Karagianis et al., 2009). However, this study cannot be generalized to olanzapine-naïve patients. Moreover, the study period was short. Therefore, we designed this one-year, open-label, multicenter, randomized, flexible-dose study to clarify whether or not body weight change differs between olanzapine ODT and OST treatments in olanzapine-naïve schizophrenia patients. 2. Methods 2.1. Subjects The subjects were 118 patients who fulfilled the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for schizophrenia. Consensus diagnosis was made for each patient by at least two experienced psychiatrists. They all needed to change antipsychotics because of insufficient efficacy or adverse events, or to start pharmacotherapy again because of discontinuation of the previous treatment or first episode. All participants (or their legal representatives) provided written informed consent after receiving a full explanation of the study procedures. 2.2. Study design This study was conducted at the Department of Psychiatry, Hokkaido University Hospital and 19 associated hospitals (7 public general hospitals, 1 public psychiatric hospital, and 11 private psychiatric hospitals) in the Hokkaido district during June 2007 – April 2010. The study protocol was approved by the institutional review board of Hokkaido University Hospital. Patients were assigned randomly to receive olanzapine ODT or OST (a ratio of 1:1) based on the pre-defined randomization list with no matching condition using sealed envelopes. The initial dosage and dosage titration of the two forms were left to the discretion of the treating psychiatrists after considering dose equivalency of the previous antipsychotic treatment. Subjects were treated with olanzapine ODT or OST once a day after supper or at bedtime. Use of antidepressants and mood stabilizers was allowed and documented.

total cholesterol and high-density lipoprotein (HDL) cholesterol, and triglycerides were measured using the same schedule as body weight. Efficacy outcomes were determined using the Positive and Negative Syndrome Scale (PANSS) (Kay et al., 1991), Global Assessment of Functioning (GAF), The World Health Organization Quality of Life 26 (WHO-QOL26) (WHO-QOL group, 1998), and the Drug Attitude Inventory (DAI)-10 (Hogan et al., 1983). WHO-QOL26 is a 26-item, self-report measure designed to assess the quality of life. Twentyfour items measure the four domains of QOL: physical, psychological, social, and environmental. The other two items measure overall QOL and general health. Scores for each question ranged 1–5, with higher scores reflecting higher QOL. This study used the Japanese version of the WHO-QOL26, which was created by Tasaki and Nakane (1997). DAI-10, a self-report that is predictive of drug compliance, was used to evaluate the subjective experience related to the two forms of olanzapine. All assessments were conducted at baseline and at months 3, 6, and 12 or at the last visit before discontinuation of therapy. Other safety and tolerability outcomes were monitored using the UKU side effect rating scale (Lingjaerde et al., 1987) with the same schedule as those used for the other assessments. 2.4. Data analyses In cases of missing data, the last observation carried forward method was used. Unpaired t-tests were used for continuous variables. A chi square test or Fisher's exact test was used for evaluating betweengroup differences in categorical data. Repeated-measures analysis of variance (ANOVA) was used to determine within-group difference and between-group difference in body weight and DAI-10 score. All results are expressed as means and standard deviations. All statistical tests were two-tailed, with the significance level set to p b 0.05. Because the primary outcome measure was body weight in this study, data were also analyzed in those patients who completed the 12-month study using the repeated-measures ANOVA. Because the male/female distribution in the subject characteristics was significantly different between the OST and ODT groups, body weight data were analyzed separately for male and female samples. Analysis of the total sample was also conducted. 3. Results

2.3. Assessments

3.1. Patient disposition

Body weight was measured at baseline and at months 3, 6, and 12 or at the time of discontinuation of the assigned drug. Metabolic measures including blood glucose (fasting or causal), hemoglobinA1c (HbA1c),

Fig. 1 presents patient disposition: 139 patients were screened, 118 patents were randomized to receive olanzapine OST (N = 57) or ODT (N = 61); 85 patients completed the study. During the 12-

I. Kusumi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 36 (2012) 313–317

month study period, 33 patients dropped out: 17 (29.8%) from the OST group and 16 (26.2%) from the ODT group. The reasons for dropping out in the OST and ODT groups were insufficient efficacy (N = 3 and N = 5, respectively), adverse events (N = 7 and N = 7) and others (N = 7 and N = 4). No patient discontinued participation because of failure to lose weight. 3.2. Patient demographics and baseline characteristics Patient demographics at baseline are presented in Table 2, respectively. Although the share of males was significantly lower in the olanzapine ODT group than in the OST group (p = 0.010), no significant differences were found in the other patient characteristics between the two groups. Included were 18 new-onset, treatmentnaïve patients: 6 in the OST and 12 in the ODT group. The antipsychotic drugs that participants had been administered before entry into this study were mostly risperidone (N = 19 for OST and N = 15 for ODT) followed by haloperidol (N = 5 for OST and N = 4 for ODT), quetiapine (N = 3 for OST and N = 5 for ODT), aripiprazole (N = 2 for OST and N = 3 for ODT), and others. Patient characteristic data at baseline are presented in Table 3. Fasting blood glucose and total cholesterol were significantly higher in the ODT group than in the OST group, although HbA1c was lower. No significant difference was found in any other measure between the two groups. The mean dosages of olanzapine OST and ODT were not significantly different at any visit (9.6 ± 4.9 mg and 11.2 ± 5.2 mg at baseline, P = 0.10; 15.2 ± 5.7 mg and 14.8 ± 6.7 mg at month 3, P = 0.75; 16.1 ± 5.3 mg and 15.0 ± 6.5 mg at month 6, P = 0.38; 15.7 ± 6.2 mg and 15.2 ± 6.4 mg at month 12, P = 0.70, respectively). The shares of patients who were co-administrated antidepressants or mood stabilizers did not differ between the OST and ODT groups (Table 2). Four patients were co-administrated two or more mood stabilizers in the ODT group. 3.3. Changes in body weight and metabolic measures Changes in body weight over 1 year in the OST and ODT groups are presented in Table 4. In data from all subjects, no significant difference was found between the two groups in weight change from baseline at month 3, 6, or 12. Similar results were obtained for data related to body weight from patients who completed the 12-month study. When data related to body weight were analyzed separately for male and female samples, the results were almost identical to those of the total sample. Although the change in weight gain at month 6 was significantly higher in the OST group than in the ODT group for

315

Table 2 Patient demographics at baseline.

Number Age (years) Gender (% male) Duration of illness (years) Treatment situation (% inpatient) Family history of diabetes (%) Drug free before entry (%) Antipsychotic dose before entry Chlorpramazine equivalent (mg) Concomitant medications Antidepressants Fluvoxamine Sertraline Proxetine Milnacipran Trazodone Clomipramine Mood stabilizers Valproate Lithium Carbamazepine

OST

ODT

p value

57 43.8 ± 12.9 61.4 16.4 ± 14.5 66.6 3.5 21.1 636.2 ± 476.6

61 44.3 ± 14.0 37.7 16.9 ± 14.2 63.9 4.9 34.4 725.9 ± 584.6

0.87 0.010 0.85 0.99 0.72 0.11 0.44

7 (12.3%) 1 1 0 2 2 1 12 (21.1%) 7 2 3

5 (8.2%) 2 1 2 0 0 0 8 (13.1%) 7 2 4

0.46

0.25

male completers, reanalysis using the repeated-measures ANOVA indicated a significant time effect [F(3,40) = 3.20, P = 0.033], but not a group effect [F(1,42) = 3.21, P = 0.081] or a group × time interaction [F(3,40) = 0.57, P = 0.64]. No significant difference was observed in weight change between the two groups when analyzing only those data from treatment-naïve patients (data not shown). Although subjects treated with concomitant medications showed higher body weight at baseline than treatment-naïve subjects, weight change during study period did not significantly differ between both subject groups (data not shown). Changes from baseline at month 12 in the other metabolic measures are presented in Table 5. No significant difference was found between the two groups in change from baseline for fasting or causal blood glucose, HbA1c, total cholesterol or HDL cholesterol, or triglycerides. 3.4. Efficacy and quality of life At baseline, PANSS, GAF, DAI-10, and WHO-QOL26 scale scores were not significantly different between the groups (Table 3). No significant differences in the change from baseline in these efficacy measures

Fig. 1. Flow diagram of patient selection.

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Table 3 Patient characteristics at baseline.

Body weight (kg) Fasting glucose (mg/dL) Causal glucose (mg/dL) HbA1c (%) Total cholesterol (mg/dL) HDL-cholesterol (mg/dL) Triglycerides (mg/dL) PANSS total score GAF score DAI-10 score WHO-QOL26 score

Table 5 Changes from baseline at 12 months in various measurements. OST

ODT

p value

60.0 ± 11.8 84.4 ± 9.9 108.3 ± 19.9 5.3 ± 0.4 169.5 ± 35.0 52.4 ± 14.1 91.6 ± 50.1 91.4 ± 23.8 37.6 ± 12.5 2.6 ± 4.9 2.5 ± 0.9

59.3 ± 12.9 90.3 ± 10.5 108.5 ± 20.5 5.1 ± 0.3 183.1 ± 36.0 52.6 ± 13.8 105.3 ± 59.6 94.4 ± 22.7 37.7 ± 13.9 1.8 ± 4.5 2.5 ± 0.7

0.80 0.016 0.98 0.045 0.046 0.95 0.20 0.48 0.98 0.41 0.95

except DAI-10 were observed between the two groups at month 12 (Table 5). Although the change in DAI-10 score was significantly higher in the ODT group than in the OST group, reanalysis using the repeatedmeasures ANOVA indicated a significant time effect [F(3,99) = 6.53, P = 0.0004], but not a group effect [F(1,101) = 0.007, P = 0.93] or a group× time interaction [F(3,99) = 1.98, P = 0.12]. 3.5. Safety For each treatment group, seven patients were discontinued during study period from the reasons related to adverse events. One OST-treated patient committed suicide at 10 weeks. It is not clear whether this severe adverse event was due to non-adherence or not because serum level of olanzapine was not assessed. Three OSTtreated and four ODT-treated patients wished to quit the study because of weight gain. The other reasons for discontinuation were liver dysfunction (N = 1), hypersedation (N = 1) and akathisia (N = 1) in the OST group, and akathisia (N = 1), somnolence (N = 1) and headache (N = 1) in the ODT group. Adverse events which did not result in discontinuation were fatigue (N = 1) and tremor (N = 1) in the OST group, and akathisia (N = 2), Parkinsonism (N = 1), orthostatic hypotension (N = 1) and somnolence (N = 1) in the ODT group. 4. Discussion This 12-month, multicenter, randomized, open-label study for olanzapine-naïve patients with schizophrenia revealed no significant change in body weight between the olanzapine OST and ODT groups. The present findings contrast with those described in a series of reports: patients treated with olanzapine OST gain more body weight than those treated with ODT (Arranz et al., 2007; Chawla and

Fasting glucose (mg/dL) Causal glucose (mg/dL) HbA1c (%) Total cholesterol (mg/dL) HDL-cholesterol (mg/dL) Triglycerides (mg/dL) PANSS total score GAF score DAI-10 score WHO-QOL26 score

OST

ODT

p value

+ 0.3 ± 12.1 + 4.3 ± 14.1 + 0.3 ± 1.1 + 10.0 ± 26.1 − 1.6 ± 10.6 + 25.6 ± 68.5 − 13.5 ± 18.1 + 15.3 ± 16.7 + 0.8 ± 4.7 + 0.3 ± 0.5

+ 6.9 ± 16.1 + 3.3 ± 12.2 + 0.1 ± 0.2 + 13.0 ± 36.4 − 0.03 ± 10.3 + 33.2 ± 80.2 − 16.0 ± 21.5 + 15.9 ± 20.0 + 3.1 ± 4.9 + 0.3 ± 0.5

0.16 0.87 0.43 0.73 0.36 0.49 0.51 0.87 0.021 0.61

Luxton-Andrew, 2008; Crocq et al., 2007; De Haan et al., 2004). However, Karagianis et al. (2009) in the same research group reported recently that patients receiving ODT experienced a similar mean change in BMI and body weight from baseline to those receiving OST during a 16-week, randomized, controlled study. The subjects in that study had already gained body weight during prior olanzapine OST treatment and were not olanzapine-naïve patients. Olanzapine is well known to tend to increase body weight early in the course of treatment (Kinon et al., 2005). Consequently, the present report is the first to describe a study randomly comparing the two dosage forms related to their effects on body weight and metabolic measures in olanzapine-naïve schizophrenia patients. The present findings were in accord with the results of some recent studies. Vidarsdottir et al. (2010a; 2010b) compared the effect of 8-day treatment with olanzapine OST and ODT on glucose, lipid metabolism and various gut hormone secretion in healthy male subjects in a randomized crossover design. Consequently, both formulations similarly affected all these measurements. A 12-week randomized, crossover, open-label study comparing the preference for olanzapine OST with ODT in schizophrenia outpatients showed almost identical proportions of weight increase (6.0% vs. 7.6%) although the body weight itself was not reported (Bitter et al., 2010). In that study, no significant change was found in the DAI-10 score between formulations, although significantly more patients preferred ODT (61%) to OST (27%). In the present study, which was conducted over a longer period, no significant difference in effect on DAI-10 score was found between the two groups based on results of repeatedmeasures ANOVA. Moreover, our present findings suggest no significant differences in efficacy such as PANSS or GAF scores, QOL, or adverse events between the two treatments. Our study has several limitations. First, because the sample was small, we might have failed to detect slight differences in weight gain in olanzapine OST and ODT groups. Second, because this was a

Table 4 Change in body weight during 1 year in OST and ODT groups. Overall

Completers

OST (N) All patients 3M 6M 12 M Male patients 3M 6M 12 M Female patients 3M 6M 12 M N: number

57 49 42 40 35 31 27 26 22 18 15 14

ODT kg + 1.2 ± 2.8 + 1.9 ± 3.9 + 3.0 ± 4.7 + 1.1 ± 3.1 + 1.4 ± 4.3 + 2.5 ± 4.9 + 1.6 ± 2.3 + 2.8 ± 2.9 + 3.8 ± 4.2

(N) 61 55 49 45 23 19 15 13 38 36 34 32

p kg

OST (N)

+ 1.0 ± 3.8 + 0.8 ± 4.5 + 1.8 ± 5.5

0.69 0.11 0.07

− 0.2 ± 4.7 − 0.3 ± 5.6 + 1.5 ± 5.8

0.28 0.26 0.54

+ 1.6 ± 3.1 + 1.4 ± 3.8 + 1.9 ± 5.4

0.94 0.23 0.25

40 40 40 40 26 26 26 26 14 14 14 14

ODT kg + 1.3 ± 2.7 + 2.0 ± 2.7 + 3.2 ± 3.8 + 1.2 ± 2.9 + 1.7 ± 2.7 + 2.9 ± 3.5 + 1.7 ± 2.3 + 2.5 ± 2.9 + 4.0 ± 4.6

(N) 45 45 45 45 13 13 13 13 32 32 32 32

p kg + 0.9 ± 3.6 + 0.5 ± 4.3 + 1.6 ± 5.6

0.57 0.08 0.14

− 1.1 ± 4.3 − 1.2 ± 5.3 + 1.2 ± 6.0

0.07 0.03 0.30

+ 1.7 ± 2.9 + 1.1 ± 3.8 + 1.7 ± 5.5

0.99 0.29 0.24

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randomized but open-label study, both clinicians and patients might have had expectations about the therapeutic potency and side-effect profile of each form of olanzapine. For those reasons, a doubleblinded study in a larger sample must be undertaken to replicate the findings of this study. Third, we obtained no data for the height of participants. Consequently, we failed to analyze the change of body mass index (BMI) in this study. Reportedly, BMI reflects adiposity better than body weight alone, and BMI at baseline has been described as a predictor for antipsychotic-induced weight gain in previous reports (Gebhardt et al., 2009; Saddichha et al., 2008). Thus, the lack of BMI measurements fairly limits interpretation of our results. Fourth, for the demographics of patient population, the ratio of females to males was different between the OST and ODT groups, which might affect the results. Moreover, most subjects in this study were patients with chronic schizophrenia whereas adolescent or first-episode patients were examined in some previous reports. This discrepancy might result in the different conclusion and be involved in the fact that weight changes induced by olanzapine OST and ODT in this study were less than those in the previous studies. Finally, medication-naïve patients were only a part of participants and more in the ODT group than in the OST group although it is not statistically significant. Moreover, we could not check how long the drugs that might affect body weight had been continued before the entry of this study. Drugs used over a long period might have affected the results obtained in this study. In conclusion, in contrast to results of previous studies, this 12month, multicenter, randomized, open-label study in olanzapinenaïve patients with schizophrenia showed no significant difference in body weight gain, metabolic measures, efficacy, QOL, subjective experience or tolerability between the olanzapine OST and ODT treated groups. Conflict of interest The authors have no direct financial support relevant to this study. Dr. Kusumi receives honoraria from Eli Lilly and serves as an advisory board member of Dainippon Sumitomo Pharma and Mitsubishi Tanabe Pharma. Dr. Koyama receives honoraria from Astellas and Eli Lilly, and receives a research grant from Dainippon Sumitomo Pharma and Astellas. Other authors declare that they have no conflict of interest. Contributors Dr. Kusumi designed the study and wrote the first draft of this manuscript. Dr. Honda, Dr. Uemura, Dr. Sugawara, Dr. Kohsaka and Dr. Tochigi collected the data and contributed to the development of the manuscript. Dr. Koyama supervised the study design. Acknowledgements The authors would like to express their appreciation to the following collaborating investigators: Shinohara K from Sapporo Suzuki Hospital, Sapporo; Sugawara M and Mitsuda T from San-ai Hospital, Noboribetsu; Niwa Y, Ogawa T and Akimoto T from the Department of Psychiatry, Kushiro City General Hospital, Kushiro; Furukata M, Shirai Y and Iwata K from the Department of Psychiatry, Wakkanai City Hospital, Wakkanai; Takeshige H and Okazaki D from Hokkaido Koyogaoka Hospital, Abashiri; Watanabe S from Nakae Hospital, Sapporo; Niide Y and Miyake T from the Department of Psychiatry, Yakumo General Hospital, Yakumo; Ishikane T from Ishikane Hospital, Sapporo; Horiguchi K and Iwata A from Kutchan-Kosei General Hospital, Kutchan; Hayashishita T from Hayashishita Hospital, Sapporo; Usukubo Y and Ito K from Sapporo Hanazono Hospital, Sapporo; Togashi Y, Miyamoto K and Ikeda T from Soen Hospital, Sapporo; Fujiwara Y and Kaji N from the Department of Psychiatry, Iwamizawa

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