Received: 13 October 2021

| Revised: 6 January 2022 | Accepted: 7 February 2022

DOI: 10.1002/npr2.12244

ORIGINAL ARTICLE

Efficacy of clozapine for long-­stay patients with treatment-­
resistant schizophrenia: 4-­year observational study
Kentaro Mizuno1| Emiko Mizuno1 | Akira Suekane2 | Toshiaki Shiratsuchi1

1

Wakakusa Hospital, Miyazaki, Japan

2

Emergency Department, Miyazaki
Prefectual Miyazaki Hospital, Miyazaki,
Japan
Correspondence
Kentaro Mizuno, Wakakusa Hospital, 7-­37
Miyata-­chou, Miyazaki-­shi, Miyazaki 880-­
0804, Japan.
Email: kmizuno@miyazaki-wakakusa.or.jp

Abstract
Aim: Supporting patients upon discharge following prolonged hospitalization in private psychiatric hospitals in Japan have long been an issue. This study evaluated theefficacy of clozapine in treating long-­stay patients with treatment-­resistant schizophrenia to reduce the frequency and duration of readmissions postdischarge.
Methods: We retrospectively examined the length and frequency of hospitalizationsof long-­stay and non-­long-­stay patients with schizophrenia who were introduced toclozapine at our hospital.
Results: Comparing participants’ medical records 2 years before and after the introduction of clozapine, we identified a significant decrease in both length and frequencyof hospitalizations in all patients who were introduced to clozapine. In long-­staypatients, the length and frequency of hospitalization were significantly reduced.
However, compared to non-­long-­stay patients, the period from introduction of clozapine to discharge was longer and the dose of clozapine was higher. Thus, it is necessary to take time to evaluate the therapeutic effects for long-­stay patients.
Conclusion: The results showed that clozapine is helpful for patients with treatment-­
resistant schizophrenia, who are considered difficult to treat and discharge in Japan.
KEYWORDS

clozapine, drug therapy, hospitalization, schizophrenia, treatment outcome

1|

I NTRO D U C TI O N

TRS patients by 2025.3 However, as of May 28, 2021, the total number of patients registered on the Clozaril Patient Monitoring Service

Clozapine (CLZ) is an antipsychotic drug that has been recommended

was 12 215; although this figure is gradually increasing, the number offor use in the treatment of treatment-­resistant schizophrenia (TRS)

patients registered each year has only reached 2000. In addition, the1since 1988, when it was proved to be effective. In Japan, CLZ has

treatment adherence rate is approximately 70%.4 Assuming that there

been covered by insurance since July 2009. CLZ has been regarded

are 200 000 TRS patients in Japan, the rate of prescription has not yet

as an important therapeutic tool to facilitate the transition of TRS pa-

reached 5%.5,6 Thus, although measures to promote the use of CLZ

2tients from hospital settings to the community in Japan. The Ministry

have been adopted in recent medical plans and medical fee revisions,7,8of Health, Labour and Welfare has set targets for infrastructure devel-

it remains a challenge to reach the targets set by the Ministry of Health,opment based on the demand for hospitalization in psychiatric facili-

Labour and Welfare. The reasons for the lack of widespread introduc-ties and the degree of success in community transition. The Ministrytion of CLZ in Japan relate to concern about blood disorders such asaims to increase the prescription rate of CLZ from 25% to 30% forleukopenia and agranulocytosis, and the short intervals between blood

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium,provided the original work is properly cited.
© 2022 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of
Neuropsychopharmacology.
Neuropsychopharmacology Reports. 2022;00:1–8.	﻿

wileyonlinelibrary.com/journal/nppr

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MIZUNO et al.

tests compared with protocols overseas, which place a burden on both

start of CLZ treatment, and for 2 years thereafter. Therefore, 286

medical personnel and patients. However, the frequency of leukope-

patients who enrolled in the Clozaril Patient Monitoring Service

nia was found to be highest during the first 18 weeks following thefrom December 28, 2009, to May 27, 2018, were included in theinitiation of CLZ. Additionally, over 90% of leukopenia cases occurredstudy. All participants had been diagnosed with TRS and under-

within 1 year of introduction of CLZ, indicating that there is little needtook CLZ treatment. Of these, 28 re-­enrolled patients and 25

to continue worrying about blood disorders during the maintenancepatients for whom follow-­up was not possible after introduction

phase of treatment.3 Furthermore, blood test intervals have been

were excluded, and 233 patients were included in the statisticalrevised to be similar to those overseas from June 2021; patients areanalysis. These 233 patients were divided into two groups, 55 in

now able to take CLZ with a test interval of 4 weeks if they meet thethe long-­s tay group and 178 in the non-­long-­s tay group, and theirconditions post 52 weeks following the introduction of CLZ. Despite adata were compared. The definitions of the long-­s tay and non-­gradual lowering of hurdles regarding CLZ prescription and usage, thelong-­s tay groups were as follows: Patients who had been hospital-

reality remains that the target is not being reached. This may be due

ized for more than 1 year in the 2 years prior to the introduction

in part to the hesitancy surrounding its use following the results of aof CLZ were included in the long-­s tay group, and the remaining

9

recently reported meta-­analysis based on randomized control trials

patients were included in the non-­long-­s tay group. In Japan, there(RCTs) conducted overseas, which questioned the superiority of CLZ.

are 170 000 long-­term inpatients who have been hospitalized for

Therefore, it is important to correctly evaluate the usefulness of CLZ

more than 1 year, of which difficulties with discharge are experi-in Japan to promote its prescription and use.

enced in 30% owing to a lack of residential and support systems,

The introduction of CLZ is not widespread, even though there are

10% because of physical complications from treatment, and thenumerous patients with schizophrenia in Japan who have been hos-remaining 60% owing to extremely severe or unstable psychiatricpitalized for 1 year or longer (long-­stay patients). Long-­stay patients

symptoms. Although CLZ is expected to be widely used as a treat-

not only have chronic and entrenched symptoms but also exhibit ament for TRS, there are no reports of its use in long-­term hospital-

decline in daily living and social skills due to long-­term hospitaliza-

ized patients, and the usefulness of CLZ for long-­term hospitalized

tion. Accordingly, the patients tend to lose confidence and motiva-

patients has not yet been demonstrated. However, we hold thattion to leave the hospital. In addition, it is difficult for patients to live

CLZ should be introduced to improve psychiatric symptoms inin the community after being discharged, and they often fall into along-­s tay hospitalized patients. In this study, we investigated the“revolving door phenomenon” of repeated readmissions due to re-effects of CLZ on shortening the length of hospitalization and pre-lapse. Both the patient and the medical personnel may have lowered

venting re-­hospitalization in long-­s tay hospitalized patients.

motivation for the new pharmacotherapy. Therefore, there may becases in which CLZ cannot be introduced as an active treatment for
long-­stay patients. Since December 2009, our institutional policy has

2.2 | Definition of periods

ensured that we actively explain the introduction of CLZ to patientsand their families who meet the criteria for TRS and introduce CLZ

The preintroduction period was defined as 2 years before the be-to patients who give their consent. As a result, the ratio of the num-

ginning of CLZ introduction, and the postintroduction period was

ber of patients hospitalized for more than 1 year to the total number

defined as 2 years from 18 weeks following CLZ introduction. Theseof hospital beds has decreased from approximately 40% to approxi-

18 weeks were regarded as the base period, in consideration of themately 10% over the past 10 years, and the number of hospital beds

principle that CLZ treatment requires hospitalization for 18 weeks

has been reduced by 40%, as reported previously.10 We have gainedin Japan and a withdrawal period from any previous drugs. The 1st

extensive experience in using the drug with long-­stay patients, andyear of the preintroduction period was defined as Year 1, the 2nd

although discharge coordination was often difficult and required ayear of the preintroduction period (up to the day before the start ofsubstantial amount of time and manpower, fewer cases of readmis-

introduction) as Year 2, the period from 18 weeks following the startsion were observed among the discharged patients. The purpose ofof CLZ introduction to 1 year after the start of introduction as Year

this study was to demonstrate the effectiveness of CLZ in reducing

3, and the 1 year following Year 3 as Year 4.

the length of hospital stay and prevent re-­hospitalization by comparing the number of hospital stays before and after the introductionof CLZ.

2|

M E TH O D S

2.1 | Sample

2.3 | Ethical considerations
This study was approved by the ethics committee of the Wakakusa
Hospital (approval number 2020-­0 01). Medical records of eligible
patients from December 28, 2007, to September 30, 2020, wereanalyzed. The purpose of this study and the process to request exclusion were posted in the hospital, and an adequate opt-­out period

To be included in the study, patients had to have been observed

was provided. Data were anonymized such that individuals could notfor 2 years before the introduction of CLZ, for 18 weeks after thebe identified.

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MIZUNO et al.

2.4 | Research designon these variables. The estimated CLZ dose adherence rates wereThis mirror-­image study retrospectively examined changes in bothused to compare the length and frequency of hospitalizations before

the length and number of hospitalizations over a period of 2 years

and after the introduction of CLZ. The significance value was set at

before and after the introduction of CLZ. The effects of CLZ

0.05.

calculated using log-­rank tests. The Wilcoxon signed-­rank test waswere compared between the long-­stay and non-­long-­stay groups(Figure 1).

3|

R E S U LT S

2.5 | Data collection

3.1 | Sample characteristics

In terms of demographic and background details, we collected data

Table 1 shows the background details of the full sample, and theon gender, duration of illness, age at the start of treatment, reason(s)long-­s tay and non-­long-­s tay groups. The total number of patientsfor introduction of CLZ, and dosage of antipsychotic drugs before

surveyed was 233 (117 male, 116 female). The median age at the

introduction of CLZ. The Clinical Global Impression Scale-­Severity

time of CLZ introduction was 43 years, the median illness dura-(CGI-­S) was administered at the time of introduction of CLZ and attion was 20 years, the median chlorpromazine-­e quivalent antip-

the time of discharge. The CGI-­S is a 7-­point scale that requires thesychotic dose before CLZ introduction was 800 mg, the medianclinician to rate the severity of a patient's illness at the time of as-

CGI-­S at time of CLZ introduction was 6, and the median duration

sessment, relative to the clinician's past experience with patientsof CLZ treatment was 1925 days. A total of 230 patients (98.7%)

who have the same diagnosis (1. normal, 2. borderline, 3. mildly ill, 4.

were discharged during the study period; in terms of medianmoderately ill, 5. markedly ill, 6. severely ill, and 7. most extremely

values of the entire group, the CLZ dose at first discharge was

11ill). CLZ dose at the time of discharge or at the end of the study was

200 mg, and the duration of hospitalization from CLZ introduction

recorded along with the number of days between the introduction of

to discharge was 124.5 days. The frequency of hospitalization for

CLZ and discharge, and the duration of CLZ administration. Details

2 years after CLZ introduction was 1, and CGI-­S at discharge was 4.

regarding CLZ treatment adherence, the length of stay, and the fre-In a comparison between the long-­s tay and non-­long-­s tay groups,

quency of readmission in the long-­stay and non-­long-­stay groups

there were no significant differences in age at introduction, sex,

were also recorded.

illness duration and antipsychotic dose before the introduction,
frequency of hospitalization for 2 years after CLZ introduction,

2.6 | Data analysis

CGI-­S before introduction, adherence rate, or CGI-­S at discharge.
However, there were significant differences in the duration of CLZ
administration, length of hospitalization in the 2 years before in-

The data were analyzed using EZR version 1.54.12 The data were

troduction, CLZ dose at discharge, and duration of hospitalization

tested for normality, and it was found that the duration of disorder,

between introduction and discharge. The median duration of CLZage, CLZ dose and dosing period, CGI-­S, duration of hospitalization

treatment was 2696 days in the long-­s tay group versus 1722 days

until discharge, length of hospitalization before and after introduc-in the non-­long-­s tay group, with a significantly longer duration fortion of CLZ, and number of instances of hospitalization were not

the long-­s tay group (P < .0001). The median length of hospital staynormally distributed. Accordingly, the Mann–­Whitney U test wasin the long-­s tay group was 665 days, whereas it was 108 days inused to compare the long-­stay group with the non-­long-­stay groupthe non-­long-­s tay group, signifying a significantly longer period

F I G U R E 1 Period for evaluation of effectiveness. The preintroduction period was defined as 2 years before the beginning of CLZ
treatment, and the postintroduction period was defined as 2 years from the 18 weeks following CLZ introduction. The 1st year of thepreintroduction period was defined as Year 1; the 2nd year of the preintroduction period (up to the day before the start of introduction) was
defined as Year 2; the period from 18 weeks following the start of CLZ introduction to 1 year after the start of introduction was defined asYear 3, and the 1 year following Year 3 was defined as Year 4

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MIZUNO et al.

TA B L E 1 Patient background data
Background Information

All subjects(n = 233)

Long-­stay group(n = 55)

Non-­long-­stay group(n = 178)

P value

No. of males (%)

117 (50.2%)

32 (57.1%)

85 (48.0%)

0.236

Age at introduction

43 (33, 51)

43.5 (32.75, 54)

42 (34, 50)

0.785

Duration of illness (years)

20 (12, 28)

22 (12.75, 31)

20 (12, 26)

0.136

Antipsychotic dose before CLZ (mg: CPZ
equivalent)

800 (600, 900)

800 (600, 868.75)

800 (600, 900)

0.856

CGI-­S before introduction of CLZ

6 (6, 6)

6 (6, 6)

6 (6, 6)

0.066

Duration of CLZ treatment (days)

1925 (949, 2765)

2696 (1832.75, 3179.75)

1722 (909, 2562)<0.0001**

Length of hospitalization in the 2 years prior
to CLZ introduction (days)

163 (68, 349)

665 (489.25, 730)

108 (44, 190)

<0.0001**

Adherence rate (%)

70.4

73.2

69.5

0.597

Information at discharge

All subjects(n = 230)

Long-­stay group(n = 54)Non-­long-­stay group(n = 176)

P value

CLZ dose at discharge (mg)200 (100, 300)300 (200, 350)

200 (100, 300)

<0.001**

Length of hospitalization from introductionof CLZ to discharge (days)

124.5 (76.25, 196)

215.5 (146.25, 494.25)

101 (69.75, 155.5)<0.0001**

Frequency of hospitalization

1 (0, 2)

1 (0, 2)

1 (0, 2)

0.445

CGI-­S at discharge

4 (4, 4)4 (4, 5)

4 (4, 4)0.111

Note: Median (lower quartile and upper quartile).
**P < .01.

the introduction of CLZ to hospital discharge was 215 days in thelong-­s tay group and 101 days in the non-­long-­s tay group, indicating a significantly longer time for the long-­s tay group (P < .0001).

3.2 | Treatment adherence rate
The estimated CLZ treatment adherence rates in the long-­stay andnon-­long-­stay groups are shown in Figure 2. A total of 69 patients(29.6%) discontinued CLZ treatment after introduction. The overall
estimated treatment adherence rate was 83.3% (95%, CI: 77.8%-­
87.5%) at 1 year, 79.4% (95%, CI: 73.6%–­8 4.0%) at 2 years, and73.9% (95%, CI: 67.5%-­79.1%) at 5 years. The estimated treatment
adherence rate was not significantly different in the long-­stay andnon-­long-­stay groups (P = .278), and the estimated adherence rate
at 2 years was 83.9% in the long-­stay group and 77.4% in the non-­long-­stay group.

F I G U R E 2 Estimated CLZ treatment adherence rate. Clozapine
treatment continuation rates among patients. A Kaplan–­Meiersurvival plot for the rate of clozapine treatment continuation. Lines
represent the long-­stay group (—­) and the non-­long-­stay group (—­)

3.3 | Comparison of the length and frequency of
hospitalizations before and after the introduction of
CLZ in the long-­stay and non-­long-­stay groups
The length of hospitalization at years 1, 2, 3, 4, and 18 weeks after

for the long-­stay group (P < .0001). The median CLZ dose at

the start of the introduction is shown in Table 2. Figure 1 shows thethe time of discharge was 300 mg in the long-­s tay group versus

length of hospitalization of the whole sample, the long-­stay group,

200 mg in the non-­long-­s tay group, with the long-­s tay group re-and the non-­long-­stay group in Years 1 and 2 (before the introduc-

ceiving a significantly higher dose (P < .001). The median time fromtion of CLZ), Years 3 and 4 (after the introduction of CLZ) and during

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MIZUNO et al.

the base period. The frequency of hospitalization was also comparedlength and frequency of hospitalizations decreased when CLZ wasin the same manner. Table 3 shows the length and frequency of hos-combined with other antipsychotics for CLZ-­refractory patients.13

pitalizations of the whole sample, and of the long-­stay and non-­long-­

In Japan, however, the use of CLZ in combination with other antip-

stay groups, before and after the introduction of CLZ.

sychotics is prohibited in principle, as instructions in the package

Both long-­stay and non-­long-­stay groups showed significant de-inserts of prescription drugs and the recommended treatment forcreases in the length and frequency of hospitalizations after intro-

CLZ-­refractory patients suggest CLZ combined with lamotrigine or

duction (P < .001).

modified electroconvulsive therapy (m-­ECT),14 m-­
ECT combined4|with other antipsychotics,15 or the use of antipsychotics other than
CLZ as a monotherapy or in combination with antipsychotics.16

DISCUSSION

However, as shown in overseas reports, reintroduction of CLZ, or

4.1 | Treatment adherence rate and reasons fordiscontinuation
Inada, Oshibuchi, Ishigooka, and Nishimura reported the estimated2-­year adherence rate of CLZ in Japan based on the Clozaril Patient
Monitoring Service registry data. The continuation rates of CLZ

a combination of CLZ with other antipsychotics, may be worth exploring for patients who discontinued CLZ for reasons other thanagranulocytosis or leukopenia.

4.2 | Decrease in the length and frequency of
hospitalization

treatment after all-­cause discontinuation were 78.2% and 72.9% at
1 and 2 years after treatment initiation, respectively.4 Our observa-

Our results showed that the introduction of CLZ significantly re-tional study showed similar results, with a high adherence rate even

duced the length and frequency of hospitalization. Decrease in theafter 2 years. Regarding the group that discontinued, the majority

length and frequency of hospitalizations are often used as indica-of discontinuations occurred within 1 year after introduction, andtors in studies investigating the usefulness of CLZ. In Japan, Misawa,

most discontinuations occurred due to agranulocytosis or leuko-

Suzuki, and Fujii investigated the length of hospitalization and de-penia during this period. The CGI-­S at discharge was significantly

gree of isolation during the 1st year after the introduction of CLZ.17

higher among those who discontinued treatment than among those

The authors reported that there was no significant decrease in the

who adhered to the CLZ treatment, indicating that some patients

length of hospitalization, but there was a significant decrease in thewere refractory to CLZ. Among the CLZ-­refractory patients at ourfrequency of isolation, thereby supporting the usefulness of CLZ.

hospital, alternate treatment plans involving other antipsychotics

Our study reported different reductions as opposed to those re-and electroconvulsive therapy were attempted. However, treatment

ported by Misawa et al17 in the length of hospitalization before andwith alternate antipsychotics was not successful for some patients

after the introduction of CLZ. One of the reasons for this may be theand they were reintroduced to CLZ. It has been reported that thelarger sample size of this study. In contrast to the 35 participants in

TA B L E 2 Length of hospitalization in each period
All subjects(n = 233)

Long-­stay group(n = 55)

Non-­long-­stay group(n = 178)

Length of hospitalization (days)

47 (0, 189)

365 (250.5, 365)

11 (0, 74)

Frequency of hospitalization

0 (0, 1)0 (0, 1)0 (0, 1)

Length of hospitalization (days)

100 (34, 213)

365 (280.5, 365)

67 (17, 123)

Frequency of hospitalization

1 (1, 2)

1 (0, 1)1 (1, 2)

Length of hospitalization (days)

126 (78, 126)

126 (126, 126)

103.5 (72, 126)

Frequency of hospitalization

0 (0, 0)0 (0, 0)0 (0, 0)Length of hospitalization (days)

62 (0, 154)

165 (78.5, 365)

39 (0, 95)

Frequency of hospitalization

0 (0, 1)0 (0, 1)0 (0, 1)

Length of hospitalization (days)

0 (0, 85)

77 (0, 212)

0 (0, 53.75)

Frequency of hospitalization

0 (0, 1)0 (0, 1)0 (0, 1)

Year 1

Year 218 weeks after startYear 3

Year 4

Note: Median (lower quartile and upper quartile).

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MIZUNO et al.

TA B L E 3 Comparison of the length and frequency of hospitalization before and after introduction of CLZ
Before introduction

After introduction

P value

Length of hospitalization of all patients (days)

157 (51, 348)

88 (10, 241)<0.001**

Length of hospitalization of the long-­stay group (days)

684 (496.5, 730)

273 (124.5, 490)

<0.001**

Length of hospitalization of the non-­long-­stay group (days)

101 (36.25, 186.5)

64 (0, 139.5)<0.001**Frequency of hospitalization of all patients

2 (1, 3)

1 (0, 2)<0.001**Frequency of hospitalization of the long-­stay group

1 (0, 2)0 (0, 2)<0.001**Frequency of hospitalization of the non-­long-­stay group2 (1, 3)

1 (0, 1.75)<0.001**

Note: Median (lower quartile, upper quartile).
**P < .01, *P < .05.

the study by Misawa et al17 our study had a total sample size of 233,

took twice as long for the long-­stay group to be discharged from thewith 55 participants in the long-­stay group alone, making it easierhospital compared to that for the non-­long-­stay group, suggesting

to show significant differences. In addition, the survey and evalua-that the effect of treatment emerged more slowly in the long-­staytion periods of this study after the introduction of CLZ was 2 years,

group than in the non-­long-­stay group, even with the same severity

compared to 1 year in the study by Misawa et al17 Moreover, theof psychiatric symptoms. This illustrates that varied dosages and du-evaluation period after the introduction of CLZ began at 18 weeks

rations of treatment are needed to evaluate the effect of treatment

postintroduction in our study compared to 3 months postintroduc-on the long-­stay group. Thus, the treatment for the long-­stay grouption in Misawa et al17 which may have led to different results. As

was more difficult than that for the non-­long-­stay group. However,shown in Tables 2 and 3, reduction in the length of hospitalizations

the frequency of re-­hospitalization of the long-­stay group before

due to CLZ treatment tends to be more apparent over time, that is,and after the introduction decreased significantly, and a compari-more pronounced at 2 years than at 1 year. Improvement of psy-son of the number of rehospitalizations between the long-­stay andchiatric symptoms, such as improved communication and decreasednon-­long-­stay groups showed no significant difference, indicating

impulsiveness, was observed from the early stages of introduction.

that the same level of re-­hospitalization prevention effect can be

However, it takes time for patients who are accustomed to an inpa-

expected in both the long-­stay and non-­long-­stay groups. Althoughtient environment to acquire the desire to leave the hospital, and forsome environmental factors can make discharge more difficult in thetheir families and communities to prepare to accept patients who are

long-­term stay group than in the non-­long-­term stay group, such asin recovery. Therefore, if the observation period after the introduc-

the loss of a place to return and absence of a support person, thetion of CLZ is short, the effect of reducing the length and frequency

discharge rate in our hospital was not significantly different betweenof hospitalization may not be detected.

the groups. This may be due to the fact that the community collaboration (day care and home nursing) that supports patients after

4.3 | CLZ treatment for the long-­stay group
There was no difference between the long-­stay group and the non-­long-­stay group in the duration or severity of illness before the in-discharge may be effective in promoting discharge and preventing
readmission, but this is unclear as it was not the subject of this study.

4.4 | Significance of observational studies

troduction of CLZ, and both groups had similar adherence rates andimprovements in CGI-­S. Significant differences between the long-­

There are many reports of observational studies and cohort stud-

stay and non-­long-­stay groups were found in the duration of CLZ

ies on the usefulness of CLZ for TRS.18-­21 However, recent meta-­

administration, CLZ dose at discharge, and length of hospital stayanalyses based on RCTs have cast doubt on the superiority of CLZ

before discharge. The significant difference in duration of treatmentcompared with other second-­generation antipsychotics.9 It is im-

reflects the priority given to the introduction of CLZ in the long-­stay

portant to note that RCT-­b ased meta-­analyses have more reliablegroup during hospitalization. Many patients in the long-­stay groupdata than observational or cohort studies, such as the one we con-

had prolonged hospitalizations owing to lack of improvement withducted here, and that their results often show no benefit of CLZ

other antipsychotic treatments and were introduced to CLZ later,over other second-­generation antipsychotics. However, in RCTs

between 2010 and 2013. On the other hand, many patients in the

involving CLZ, participants may only include a subset of the patientnon-­long-­stay group were admitted to our hospital after that time

population with clinical symptoms requiring CLZ. In other words,

and were introduced to the CLZ sooner, which may have reflected

it has been pointed out that the problem is that only patients whoin the difference in the duration of treatment. Differences in dosage

meet the TRS criteria but have the capacity to consent to par-and the length of hospital stay may be influenced by nonmedical

ticipation in clinical trials are eligible for the trial.17 Patients who

factors such as postdischarge family and community acceptance andhave been hospitalized for a long period in psychiatric hospitals in

economic base, but these were not clarified in this study. However, itJapan, such as the long-­s tay group, cannot be discharged despite

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MIZUNO et al.

the use of various antipsychotic drugs other than CLZ, either as

this study indicate that the use of CLZ should be expanded. Further

single agents or in combination, and new treatment methods areresearch is required to determine the disadvantages of schizophrenic

required. Conducting an RCT with such a patient population faces

patients who need CLZ but lack access to it.

difficulties in securing participants in terms of their ability to consent, and also in tracking their progress over time in terms of thelength and frequency of hospitalizations. Therefore, while refer-

4.6 | Limitations

ring to the findings of RCTs, the results of retrospective observational studies such as the present study may be meaningful for the

The limitations of this study include the fact that it was a retrospec-

evaluation of the efficacy of CLZ in the long-­s tay group.

tive observational study of patients treated at a single medical facility, as opposed to a study, which was designed with a comparison

4.5 | Towards increased use of CLZ in futuregroup. Additionally, 30% of the patients were transferred to anotherfacility or completed CLZ treatment during the study period. This
study examined the effect of clozapine; as the study included a clo-

Over 10 years have passed since CLZ became available in Japan,

zapine discontinuation group, there may have been effects of drugs

and the accumulated knowledge to date has revealed that the fre-other than clozapine, and the hospitalization period and frequency

quency of leukocyte count decline is comparable to that of over-after introduction may have increased. In addition, patients who

seas countries and that over 90% of cases occur within 1-­year

have been transferred to other hospitals are excluded because thepostintroduction. Operating procedures for patients who had

subsequent progress is unknown. Therefore, in future, multifacility

been on CLZ for 52 weeks were revised such that, in principle,

research is desirable. These limitations must be considered whenmonitoring of the white blood cell count once every 4 weeks isinterpreting the results of the present study.

sufficient. In Okinawa22 and other prefectures, efforts are underway to enable and mobilize medical institutions that are concerned about the introduction of CLZ to provide treatment in the5|

CO N C LU S I O N

maintenance phase. Measures to reduce the burden on medical
institutions that oversee introduction by separating such institu-

The present study is a long-­term observational study of CLZ use in ations from those that oversee treatment in the maintenance phaseprivate single-­specialty psychiatric hospital that has continued CLZ

may help in furthering the use of CLZ. Of the TRS patients eligible

treatment, from introduction to maintenance. The results showed

for CLZ, the long-­s tay group was more frequently admitted to thethat the introduction of CLZ was effective in shortening the hospi-

chronic care ward of psychiatric hospitals. Our study found a re-talization period and preventing re-­hospitalization among long-­stay

duction in the duration of hospitalizations in the long-­s tay group,

patients for whom discharge from the hospital was difficult owing toindicating that CLZ is an effective treatment for the long-­stay

prolonged psychiatric symptoms and poor response to conventionalgroup. As a result, our hospital has restructured its organization by

antipsychotics. However, difficulties such as requiring more time

downsizing the chronic care ward, expanding the emergency psy-

for response to treatment to be observed among long-­stay patientschiatric ward, and reallocating staff to home nursing services, ascompared to non-­long-­stay patients with TRS were also highlighted.

previously reported.13,23 However, it is difficult for many private

In future, we will investigate the reason why the hospitalization pe-

psychiatric hospitals to conduct emergency psychiatric services

riod of the long-­stay group is extended, using a multifacility researchand restructure their organizations, and financial support to reor-

approach.

ganize chronic care wards may be necessary in order to encourage
the use of CLZ.
CLZ is known worldwide as a treatment for TRS, and while its use
is reported to be increasing, it is still underutilized in many countries.

AC K N OW L E D G E M E N T S
We would like to thank Editage (www.edita​ge.com) for English language editing.

Bachmann et al24 analyzed data from 17 countries and found that therate of CLZ use was 189.2 per 100 000 in Finland and 116.3 in New

C O N FL I C T O F I N T E R E S T

Zealand, compared with 42 in Italy, 14 in the USA, and 0.6 in Japan.

Kentaro Mizuno received lecture fees from Janssen Pharmaceutical,

Assuming an estimated proportion of patients with TRS of 20%–­30%

Otsuka Pharmaceutical, and Novartis Japan. All other authors de-and a prevalence of schizophrenia of 0.7%–­0.8%, the CLZ use rate

clare no conflict of interest.

should be between 140 and 240 per 100 000. In Japan, there are few
reports on the use of CLZ in schizophrenic patients who have been

AU T H O R C O N T R I B U T I O N S

hospitalized for more than a year and whose treatment has stagnated.

KM conceptualized and finalized the manuscript. K.M and AS col-In this study, we used CLZ in patients with prolonged hospitalization

lected the data and performed statistical analysis. EM created theand confirmed its effectiveness in reducing hospitalization days andfigures and tables. TS provided critical comments regarding thepreventing readmission. However, in most countries, the use of CLZ

manuscript. All authors contributed to manuscript revision and haveis limited to a subset of patients with presumed TRS. The findings ofread and approved the submitted version.

8|

MIZUNO et al.

A P P R OVA L O F T H E R E S E A R C H P R OTO C O L BY A N
I N S T I T U T I O N A L R E V I E W B OA R DThis study was approved by the ethics committee of the Wakakusa
Hospital (approval number 2020-­0 01).
I N FO R M E D C O N S E N T
Information regarding the study was posted in the hospital alongwith an explanation of how to request exclusion. Patients were
provided with an adequate period of time to opt out. Patients whochose to not opt out were considered to have provided their informed consent to participate. Data were anonymized such that individuals could not be identified.
DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are openly available
on Figshare at https://figsh​are.com/s/0d21d​f f4c6​4da39​c f27.
ORCID
Kentaro Mizuno

https://orcid.org/0000-0002-3026-3990

REFERENCES
1. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for thetreatment-­resistant schizophrenic: a double-­blind comparison withchlorpromazine. Arch Gen Psychiatry. 1988;45(9):789–­96.
2. Kentaro M, Akira S, Kyohei N, Manabu M, Emiko M, Toshiaki S. The
role of clozapine for deinstitutionalization of a private psychiatrichospital. Japanese J Clin Pharmacol. 2020;23(1):53–­61.
3. Ministry of Health, Labour and Welfare. A guide for building acommunity-­based comprehensive care system that responds tomental disorders (2020 edition) (in Japanese). [Internet]. c2020.
[cited 2021 May 6]. Reference materials 8-­
10. Available fromhttps://www.mhlw-­houka​t suca​re-­ikou.jp/ref.html#sec02
4. Inada K, Oshibuchi H, Ishigooka J, Nishimura K. Analysis ofclozapine use and safety by using comprehensive national datafrom the Japanese Clozapine Patient Monitoring Service. J Clin
Psychopharmacol. 2018;38(4):302–­6.
5. Meltzer H. Clozapine: balancing safety with superior antipsychotic
efficacy. Clin Schizophr Relat Psychos. 2012;6(3):134–­4 4.
6. Farooq S, Agid O, Foussias G, Remington G. Using treatment response to subtype schizophrenia: proposal for a new paradigm inclassification. Schizophr Bull. 2013;39:1169–­72.
7. Ministry of Health, Labour and Welfare. Revision of FY2018 medical fees; summary of the second revision: 1 (in Japanese). [Internet].
c2020. [cited 2018 Feb 7]. 302-­3 03 p. Available from https://www.mhlw.go.jp/file/05-­Shing​ikai-­12404​0 00-­Hoken​k yoku​-­Iryou​
ka/00001​93708.pdf
8. Ministry of Health, Labour and Welfare. Revision of FY2020 medical fees; summary of the second revision: 1 (in Japanese). [Internet].
c2020. [cited 2020 Feb 7]. 162-­163 p. Available from https://www.
mhlw.go.jp/conte​nt/12404​0 00/00060​1838.pdf
9. Samara MT, Dold M, Gianatsi M, Nikolakopoulou A, Helfer B, SalantiG, et al. Efficacy, acceptability, and tolerability of antipsychotics intreatment-­resistant schizophrenia: a network meta-­analysis. JAMA
Psychiatr. 2016;73(3):199–­210.
10. Mizuno K. Efforts to reduce hospital beds: synergistic effects ofclozapine and psychiatric emergency ward treatment (in Japanese).
Psychiatr Emerg Care. 2017;20:55–­8.

11. Haro JM, Kamath SA, Ochoa SO, et al. The Clinical Global
Impression-­Schizophrenia scale: a simple instrument to measure
the diversity of symptoms present in schizophrenia. Acta Psychiatr
Scand. 2003;107:16–­23.
12. Kanda Y. Investigation of the freely available easy-­to-­use software‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48(3):452–­8.
13. Tiihonen J, Taipale H, Mehtälä J, Vattulainen P, Correll CU,
Tanskanen A. Association of antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among adults withschizophrenia. JAMA Psychiatr. 2019;76(5):499–­507.
14. The Japanese Society of Neuropsychopharmacology, ed. Guidelines
for the Pharmacotherapy of Schizophrenia CQ4-­3: what should beselected as adjunctive therapy when clozapine is not sufficiently effective? (in Japanese). Tokyo: Igaku-­shoin. 2016;78–­83.
15. The Japanese Society of Neuropsychopharmacology, ed.
Guidelines for the Pharmacological Treatment of Schizophrenia
CQ4-­4: Is Modified Electroconvulsive Therapy (m-­ECT) Useful for
Treatment-­Resistant Schizophrenia When Clozapine is not Used?.
Tokyo: Igaku-­Shoin, 2016; 84-­7.
16. The Japanese Society of Neuropsychopharmacology, ed.
Guidelines for the Pharmacological Treatment of Schizophrenia
CQ4-­5: What are Effective Treatments for Treatment-­Resistant
Schizophrenia Other than Clozapine and ECT?. Tokyo: Igaku-­
Shoin, 2016: 88-­92.
17. Misawa F, Suzuki T, Fujii Y. Effect of clozapine vs other second-­
generation antipsychotics on hospitalization and seclusion: a retrospective mirror-­image study in a Japanese public psychiatrichospital. J Clin Psychopharmacol. 2017;37(6):664–­8.
18. Ahn YM, Chang JS, Kim Y, Lee KY, Kim JH, Kim SC, et al.
Reduction in hospital stay of chronic schizophrenic patients after
long-­
term clozapine treatment. Int Clin Psychopharmacol.
2005;20(3):157–­61.
19. McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients withchronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatr. 2006;163(4):600–­10.
20. Tiihonen J, Mittendorfer-­Rutz E, Majak M, et al. Real-­world effectiveness of antipsychotic treatment in a nationwide cohort of 29823
patients with schizophrenia. JAMA Psychiatr. 2017;74(7):686–­93.
21. Kesserwani J, Kadra G, Downs J, et al. Risk of readmission in patients with schizophrenia and schizoaffective disorder newly prescribed clozapine. J Psychopharmacol. 2019;33(4):449–­58.
22. Naoya K, Masaru M, Taku O, et al. Has psychiatry changed withthe advent of clozapine? regional clozapine treatment network -­an Okinawan model based on Ryukyu hospital (in Japanese). Clin
Psychopharmacol. 2018;21(11):1439–­49.
23. Kentaro M, Akira S, Kyohei N, et al. The role of clozapine for deinstitutionalization of a private psychiatric hospital (in Japanese). Clin
Psychopharmacol. 2020;23(1):53–­61.
24. Bachmann CJ, Aagaard L, Bernardo M, et al. International trends
in clozapine use: a study in 17 countries. Acta Psychiatr Scand.
2017;136(1):37–­51.

How to cite this article: Mizuno K, Mizuno E, Suekane A,
Shiratsuchi T. Efficacy of clozapine for long-­stay patientswith treatment-­resistant schizophrenia: 4-­year observational
study. Neuropsychopharmacol Rep. 2022;00:1–­8. https://doi.
org/10.1002/npr2.12244