Skip to main content
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2014 Oct 30.
Published in final edited form as: Psychiatry Res. 2013 Apr 18;209(3):406–411. doi: 10.1016/j.psychres.2013.03.014

Antipsychotic polypharmacy: a Japanese survey of prescribers’ attitudes and rationales

Taishiro Kishimoto a,b,c,d,*, Koichiro Watanabe a,e, Hiroyuki Uchida a,f, Masaru Mimura a, John M Kane b,c,d,g, Christoph U Correll b,c,d,g
PMCID: PMC3791180  NIHMSID: NIHMS461428  PMID: 23602697

Abstract

While combining antipsychotics is common in schizophrenia treatment, the literature on the reasons for antipsychotic polypharmacy (APP) is limited. We aimed to identify prescriber attitudes and rationales for APP in Japan where high APP utilization is reported. Two-hundred-seventeen psychiatrists participated in the survey, which assessed APP attitudes and behaviors. Prescribing APP to 47.7±24.7% (mean±SD) of their patients, psychiatrists reported that they were “moderately” concerned about APP. The most APP-justifiable factors were (1=“not at all” to 5=“extreme”): cross titration (4.50±0.67), randomized controlled evidence (3.67±0.83), and treatment of comorbid conditions (3.31±0.83). Conversely, APP-discouraging factors were: chronic side effects (4.14±0.64), difficulty determining cause and effect (4.07±0.74), and acute side effects (3.99±0.81). Comparing high to low APP prescribers (>50% vs. ≤50% of patients), no differences emerged regarding APP justification and concerns. In multivariate analyses, high APP use was associated with practice at a psychiatric hospital (OR: 2.70, 95%CI: 1.29-5.67, p=0.009), concern about potential drug-drug interactions (OR: 1.56, 95%CI: 1.04-2.35, p=0.031), and less reliance on case reports of APP showing efficacy (OR: 0.64, 95%CI: 0.44-0.92, p=0.017) (r2=0.111, p=0.001). High and low APP prescribers shared a comparable degree of justifications and concerns. Future research should examine the impact of cultural determinants on APP.

Keywords: Antipsychotic combination therapy, polypharmacy, attitudes, concerns, schizophrenia, survey

1. Introduction

Antipsychotic polypharmacy (APP), i.e. the concurrent treatment with more than one antipsychotic, is common practice in schizophrenia. APP rates are relatively high, with reported prevalence of around 10% to 50% (Broekema et al., 2007; Brunot et al., 2002; Clark et al., 2002; Correll et al., 2007; Faries et al., 2005; Fourrier et al., 2000; Ganguly et al., 2004; Jaffe and Levine, 2003; Kreyenbuhl et al., 2006; Procyshyn et al., 2001; Sim et al., 2004; Tapp et al., 2003; Wang et al., 2000). The APP rate in Japan is reported to be even higher (Ito et al., 1999), with a more recent inpatient survey indicating that 66.2% of them were taking 2 or more antipsychotics (Yoshio et al., 2012). According to recent meta-analysis, APP prevalence and time trends differ by region. For example, APP was higher in Asia and Europe than in North America (p<0.001); moreover, APP has increased numerically in North America (1980s: 12.7% to 2000s: 17.0%, p=0.94), while there was a significant decrease in Asia (1980: 55.5% to 2000: 19.2%, p=0.03) (Gallego et al., 2012a). Given this diverse prevalence and time trends in countries or regions, patient-driven factors are unlikely to play any primary role in the choice of APP, but other factors, such as prescribing custom, adherence to treatment guidelines or understanding of the literature may be more relevant in this dicision making process.

The evidence for APP is relatively weak and controversial. A recent meta-analysis showed that APP was superior to monotherapy in some outcome measures, however, it was difficult to draw firm conclusions due to possible publication bias, strong heterogeneity of the results and lack of data on specific psychopathology ratings and adverse effects (Correll et al., 2009). Furthermore, APP has been associated with increased adverse events and higher cost (Baandrup et al., 2012; Gallego et al., 2012b; Joukamaa et al., 2006). Therefore, established treatment algorithms only recommend antipsychotic co-treatment with clozapine as a last stage strategy (Argo et al., 2008; Buchanan et al., 2010; Canadian Psychiatric Association, 2005; Falkai et al., 2005; McGorry et al., 2005; National Collaborating Centre for Mental Health, 2010).

Despite this disconnect between the frequent APP use in clinical practice and treatment guidelines and clinical trial evidence discouraging APP, only few studies examined clinician perspectives toward APP. The reasons for APP reported by previous studies include skepticism towards the use of algorithms, nurses’ request (Ito et al., 2005), discontinued switching (Tapp et al., 2003), and aiming to reduce positive symptoms (Sernyak and Rosenheck, 2004; Tapp et al., 2003). Our recent survey, which targeted prescribers at a psychiatric teaching hospital in the US reported that high APP prescribers had more clinical experience, less concerns about APP and more likely a preferred APP choice (Correll et al. 2011). However, these studies mentioned above included relatively small sample sizes (12 to 78 prescribers), therefore the information is still limited.

In addition, there was a specific therapeutic difference in Japan due to lack of access to clozapine until 2010. Since APP trials have mostly examined clozapine in combination with another antipsychotic, guidelines only recommend APP after clozapine treatment has been unsuccessful. Therefore, the use of APP by Japanese psychiatrists and their attitudes toward APP may be different from that of US. As far as we know, this is the largest survey so far which directly targeted psychiatrists’ attitudes regarding APP.

2. Methods

2.1. Setting and Procedures

The survey was conducted between June 2009 and April 2010. Psychiatrists prescribing antipsychotics to psychiatric patients were invited to participate in the survey. A total of 40 facilities across 8 prefectures, including universities, psychiatric hospitals, and clinics participated. Since the survey did not require any patient information, the study was exempted from ethics review. This was not a random sample of clinicians/institutions, but rather an attempt was made to identify local physicians who could assist in facilitating high response rates to the surveys in a variety of representative clinical centers. The “Prescriber’s Reasons for Antipsychotic Combination Treatment Questionnaire: PRACT-Q” (Correll et al., 2011) (original version written in English) was translated into Japanese by the first author of this manuscript. The Japanese version of the survey (PRACT-Q-J) was back translated by a third person into English and it was validated by two English speakers, including the author of the original version. However, during the process of translation, some modifications were made in order to fit Japanese treatment settings or simplify the survey procedure (e.g. demographic characteristics, range of Likert scale). Moreover, although we included the clozapine-related items in the questionnaire, we made them optional questions, taking into consideration that many doctors did not have enough knowledge about clozapine. The PRACT-Q-J covers the following areas: 1) estimated percentage of patients on antipsychotic polypharmacy; 2) preferred antipsychotic combination(s); 3) estimated percentage of patients in whom conversion to antipsychotic monotherapy was attempted and whether this was successful or unsuccessful; 4) how much prescribers feel that APP is problematic (using a 7-point Likert scale: 1= “not at all” to 7= “extreme”); 5) attitudes toward 24 areas of potential benefits/justifications as well as 9 areas of risks/concerns regarding APP (using a 5-point Likert scale assessing how much prescribers felt APP was justified: 1= “not at all” to 5= “extreme”) in each of the 24 clinical situations, and assessing how concerned prescribers were (1= “not at all” to 5= “extreme”) about nine potentially problematic areas associated with APP. PRACT-Q-J was distributed in a form of a written questionnaire or excel file via email. No reimbursement for participants was offered.

2.2. Data Analyses

Descriptive statistics were used to describe the study sample and prescriber responses. We compared characteristics and attitudes of “high” vs. “low” APP prescribers. The median split of 50% of patients receiving more than one antipsychotic was used to divide study participants into “high” APP prescribers (i.e. >50% of patients) vs. “low” prescribers (i.e. ≤50% of patients). In addition to the median split, we also conducted a priori defined sensitivity analysis, where we used >10% vs. ≤10% of patients receiving APP as a cutoff in order to be consistent with the median split grouping used in the US survey (Correll et al., 2011). Distributions of all variables were inspected using histograms, q-q plots and Shapiro-Wilks tests before conducting statistical analyses. Differences in patient characteristics between groups were examined using chi-square analysis for categorical variables and ANOVA or Wilcoxon rank sum test for continuous variables. In order to avoid type I errors due to multiple comparisons, we applied Bonferroni correction within each of the subcategories of the comparisons. Furthermore, to identify significant predictors for high APP use, we conducted stepwise backward elimination multivariate logistic regression analyses, entering into the model any characteristic that was different at a level of p<0.10 between high and low APP prescribers. All analyses were two-sided with alpha was set at 0.05. Data were analyzed using JMP 5.0.1, SAS Institute Inc and SPSS 11.5.1, IBM Inc.

3. Results

3.1. Prescriber demographics

A total of 569 questionnaires were distributed throughout the country across 8 prefectures and 40 facilities. Of these, 217 (38.1%) (190 attendings, 27 residents) participated in the survey. Demographic characteristics are summarized in Table 1.

Table 1.

Clinician and Antipsychotic Treatment Characteristics in High vs. Low Antipsychotic Polypharmacy Prescribers (APP)

Characteristic (N=217) >50%
  APP
(n=90)
≤50%
  APP
(n=127)
P-value >10%
(N=193)
≤10%
(N=24)
P-value
Prescriber Demographics
 Attending clinician (N, %) 190
 (87.6)
82 (91.1) 108 (85.0) 0.18 172
 (89.1)
18 (75.0) 0.048
 Years of practice
  (years±SD)
10.5±8.6 11.7±10.6 9.7±6.9 0.11 10.7±8.8 8.8±6.1 0.31
 Practice at psychiatric
  hospital
164
 (75.6)
77 (85.6) 87 (68.5) 0.004 149
 (77.2)
15 (62.5) 0.11
Antipsychotic Cotreatment
    Frequency (% ± SD)
 Any combination 48.3±13.6 72.4±9.8 31.2±15.8 <0.001 53.4±20.9 7.2±3.4 <0.001
 SGA+SGA 47.9±25.3 48.9±24.2 47.2±26.1 0.63 48.1±25.7 46.0±22.7 0.71
 SGA+FGA 35.4±28.4 33.5±28.0 36.7±28.6 0.43 35.0±2.1 38.5±5.8 0.56
 FGA+FGA 17.2±18.1 18.1±18.2 16.5±18.0 0.52 17.4±18.4 15.4±15.4 0.61
Antipsychotic Cotreatment
History (% ± SD)
 Patients successfully
switched to monotherapy
28.3±19.1 28.4±19.2 28.3±18.9 0.97 28.1±19.6 29.8±14.1 0.69
 Patients unsuccessful switch
to monotherapy
37.0±21.8 38.4±20.5 35.9±22.7 0.41 37.7±22.4 31.0±15.7 0.16
 Switch to monotherapy not
attempted
35.2±27.4 33.3±27.2 36.6±27.6 0.39 34.7±28.1 39.2±21.5 0.45
Preferred Antipsychotic Class
Combinations (N, %)
 No preference 40 (19.0) 22 (25.3) 18(14.5) 0.032* 37 (37.0) 3 (21.4) 0.16
 SGA + FGA 102
(53.7)
40 (53.3) 62 (53.9) 0.92 55 (32.7) 11 (50.0) 0.27
 SGA + SGA 69 (36.3) 23 (30.7) 46 (40.0) 0.47 89 (53.0) 13 (59.1) 0.86
*Became insignificant after
Bonferroni correction

Chi2 or ANOVA/Wilcoxon rank sum test were used to detect differences between groups.

3.2. Prescriber practice

Psychiatrists estimated that as many as 47.7±24.7% (mean±SD) of their patients were prescribed APP. For the patients who received APP, psychiatrists did not attempt to switch to monotherapy in 35.2±27.4% of the cases, successfully switched to monotherapy in 28.3±19.1%, and tried to switch to monotherapy, but failed, in 37.0±21.8% of cases. Second-generation antipsychotic combination was most frequently prescribed form of APP (47.9±25.3%), followed by second- plus first-generation antipsychotics (35.4±28.4%). Regarding specific combinations, risperidone+levomepromazine was the most frequently prescribed antipsychotic co-treatment (14.9%), followed by risperidone+quetiapine (12.2%), risperidone+olanzapine (9.0%), risperidone+chlorpromazine (6.4%) and olanzapine+levomepromazine (4.9%). Among individual medications, risperidone was the antipsychotic most used as part of APP (54.5%), followed by levomepromazine (31.3%) and quetiapine (24.8%).

3.3. Attitudes towards antipsychotic polypharmacy

Overall, psychiatrists felt “moderately” concerned about APP (3.87±0.96). The most justified scenarios for APP were: cross-titration, randomized controlled evidence treatment of comorbid conditions and different route of administration (Table 2). Augmentation after failed clozapine, and augmentation due to intolerance to clozapine were ranked high as a justification (ranked 8th and 9th out of 24 respectively), but only 23% (50/217) of the participants answered these questions. On the other hand, the most highly rated reasons discouraging psychiatrists from APP use included the possibility for chronic side effects, difficulty determining cause and effect, acute side effects, potential for higher mortality, and potential drug-drug interactions (Table 3).

Table 2.

Prescribers’ Level of Justification for Antipsychotic Polypharmacy

Justification for
Antipsychotic
Polypharmacy
(Rating 1-5)
Total (N=217) (>50%)
(N=90)
(≤50%)
(N=127)
P-value (>10%)
(N=193)
(≤10%)
(N=24)
P-value
Antipsychotic
Treatment/History
 Cross titration 4.50±0.67 4.53±0.69 4.48±0.65 0.67 4.50±0.67 4.54±0.66 0.77
 Different route of
administration
3.28±0.94 3.34±0.99 3.25±0.89 0.49 3.29±0.96 3.29±0.69 0.99
*Augmentation after
failed clozapine
3.10±1.06 3.00±1.09
(n=26)
3.21±1.02
(n=24)
0.49 3.10±1.08
(n=48)
3.00±0.00
(n=2)
0.89
*Augmentation due
to
 intolerance to
clozapine
3.02±1.12 3.00±1.23
(n=26)
3.04±0.98
(n=23)
0.89 3.02± 1.13
(n=47)
3.00± 0.00
(n=2)
0.98
 Augmentation after 3
failed AP trial
3.01±1.13 3.06±1.16 2.98±1.11 0.65 3.06±1.16 2.67±0.82 0.11
 Aborted cross
titration as pt improved
2.96±0.82 3.01±0.86 2.92±0.79 0.43 2.96±0.83 2.96±0.75 1.00
 One AP believed
insufficient for relapse
prevention
2.95±0.98 2.92±0.98 2.97±0.99 0.69 2.96±0.99 2.92±0.93 0.85
 Reached upper dose
limit of 1st AP
2.92±0.94 2.91±0.97 2.92±0.92 0.94 2.93±0.95 2.79±0.83 0.49
 Augmentation after 2
failed AP trial
2.89±1.15 2.94±1.18 2.85±1.13 0.55 2.92±1.14 2.63±1.24 0.24
 Augmentation after 1
failed AP trial
2.86±0.98 2.92±1.04 2.81±0.95 0.42 2.90±0.995 2.50±0.89 0.061
 Recommended by
prior treating clinician
2.37±0.84 2.37±0.86 2.37±0.82 0.97 2.38±0.62 2.33±0.17 0.81
Improving Outcomes
 Treatment of
comorbid condition
3.31±0.83 3.4±0.79 3.2±0.85 0.10 3.29±0.85 3.42±0.65 0.49
 Different target
symptoms
3.16±0.89 3.27±0.89 3.08±0.89 0.14 3.19±0.90 2.92±0.78 0.15
 Enhance effect 2.89±0.84 2.94±0.86 2.87±0.82 0.50 2.91±0.86 2.79±0.59 0.51
 Minimize adverse
events
2.61±0.97 2.56±0.98 2.65±0.97 0.53 2.63±0.99 2.50±0.83 0.55
 Speed up effect 2.54±0.93 2.54±0.95 2.55±0.91 0.93 2.55±0.94 2.50±0.83 0.80
 Reduce number of
non-AP medications
2.59±0.94 2.49±0.95 2.65±0.92 0.23 2.58±0.95 2.66±0.87 0.66
 Reduce dose of 1st
AP
2.49±0.96 2.43±0.90 2.56±1.01 0.16 2.44±0.97 2.83±0.87 0.062
Level of Evidence for
APP efficacy
 Double blind
placebo controlled
trials
3.67±0.83 3.61±0.86 3.70±0.80 0.42 3.66±0.85 3.75±0.61 0.61
 Open label trials 3.19±0.80 3.11±0.88 3.25±0.74 0.24 3.20±0.82 3.13±0.91 0.67
 Case report 2.80±0.81 2.65±0.82 2.91±0.79 0.021 ** 2.83±0.81 2.58±0.83 0.17
Other
 Different
pharmacological
mechanism
3.19±0.89 3.2±0.92 3.2±0.88 0.94 3.20±0.899 3.08±0.83 0.55
 Family/patient
choice
2.77±0.88 2.8±0.87 2.7±0.88 0.70 2.88±0.877 2.63±0.88 0.40
 Clinical wisdom 2.55±0.88 2.5±0.92 2.6±0.85 0.96 2.56±0.886 2.46±0.83 0.59
*

The response was voluntary.

**

Became insignificant after Bonferroni correction

Chi2 or ANOVA/Wilcoxon rank sum test were used to detect differences between groups.

Table 3.

Prescribers’ Level of Concern about Antipsychotic Polypharmacy

Degree to
which Scenario
Discourages
Antipsychotic
Polypharmacy
Total
(N=217)
High
APP
(>50%)
(N=90)
Low APP
(≤50%)
(N=127)
P-value (>10%)
(N=193)
(≤10%)
(N=24)
P-value
General
Concern
 How
problematic is
antipsychotic
polypharmacy
(Rating 1-7)
3.87±0.96 3.93±1.02 3.84±0.91 0.49 3.87±0.97 3.9±0.90 0.84
Clinical
scenario
(Rating 1-5)
 Potential for
higher chronic
adverse events
4.14±0.64 4.10±0.61 4.16±0.66 0.53 4.12±0.64 4.25±0.61 0.35
 Difficulty
determining
cause and effect
4.07±0.74 4.09±0.67 4.05±0.79 0.67 4.03±0.75 4.33±0.64 0.059
 Potential for
higher acute
adverse events
3.99±0.81 3.94±0.76 4.02±0.83 0.47 4.01±0.78 3.83±1.01 0.31
 Potential for
higher mortality
3.91±0.87 4.00±0.84 3.84±0.87 0.18 3.91±0.87 3.91±0.85 0.97
 Potential
drug-drug
interactions
3.91±0.75 4.01±0.62 3.83±0.82 0.087 3.91±0.76 3.88±0.68 0.83
 Higher total
dosage of AP
3.79±0.76 3.81±0.75 3.76±0.78 0.61 3.83±0.74 3.46±0.88 0.026 *
 Increased risk
of
non-adherence
3.65±0.80 3.74±0.72 3.58±0.84 0.16 3.63±0.80 3.75±0.79 0.50
 Lack of
evidence base
3.54±0.91 3.63±0.99 3.48±0.86 0.24 3.57±0.93 3.29±0.75 0.16
 Increased cost 3.13±0.92 3.20±1.00 3.08±0.85 0.35 3.12±0.92 3.29±0.86 0.37
*

Became insignificant after Bonferroni correction

Chi2 or ANOVA/Wilcoxon rank sum test were used to detect differences between groups.

3.4. Predictor for higher use of antipsychotic polypharmacy

Using a median split of reported APP prescribing (i.e., “high”: >50%, “low”: ≤50%), high APP prescribing clinicians were more likely to have a practice at a psychiatric hospital [85.6% vs. 68.5%; χ2(df)=8.30(1); p=0.004]. Moreover, high APP utilizing psychiatrists reported more often no preference regarding specific antipsychotic class combinations compared to low APP psychiatrists [25.3% vs. 14.5%; χ2(df)=3.86(1); p=0.049] (Table 1). There was no difference between high and low APP utilizing psychiatrists regarding their beliefs, which justified (23/24 items) or discouraged (9/9 items) APP. High APP prescribing psychiatrists differed from low APP prescribing psychiatrists in less reliance on single case reports as a justification for APP [2.65±0.82 vs.2.91±0.79, F(df1, df2)=5.37(1,213), p=0.021] however, these difference became insignificant after Bonferroni correction (Table 2). In multivariate analyses, practice at a psychiatric hospital (OR: 2.70, 95%CI: 1.29-5.67, p=0.009), concern about potential drug-drug interactions (OR: 1.56, 95%CI: 1.04-2.35, p=0.031), and less reliance on case reports showing APP efficacy (OR: 0.64, 95%CI: 0.44-0.92, p=0.017) were associated with high APP use (r2=0.111, p=0.001).

When we used >10% vs. ≤10% as cutoff to divide psychiatrists, very low APP prescribers were less likely to be attending clinicians [89.1% vs. 75.0%; χ2(df)=3.91(1); p=0.048]; i.e., more likely to be residents (10.9% vs. 25.0%). There was no difference between the two groups regarding factors justifying (23/24) or discouraging APP (9/9). The only difference was that very low APP prescribing psychiatrists were less concerned about higher total dosage than high APP prescribing psychiatrists [3.83±0.74 vs. 3.46±0.88; F(df1, df2)=5.01(1,213); p=0.026] which became insignificant after Bonferroni correction (Table 3). In multivariate analyses, concern about higher total dosage (OR: 2.07, 1.18-3.64, p=0.011), and less concern about difficulty determining cause and effect (OR: 0.43, 95%CI: 0.22-0.84, p=0.014) were associated with high APP use (r2=0.87 p=0.008).

4. Discussion

Results from our survey showed high reported APP use in Japan. Moreover, faced with APP, psychiatrists were reluctant to convert to monotherapy in over one-third of the cases, while this was successful in 28% of the cases when attempted. Dividing psychiatrists into high vs. low APP prescribers, using the median split of 50% of their patients receiving APP as the cutoff, very few differences emerged. Practice at a psychiatric hospital was related to high reported APP utilization, which is intuitive considering the Japanese psychiatric system since more severely ill patients are seen in psychiatric hospitals compared to psychiatric units that are part of general medical hospitals. Even using 10% as a cutoff in order to be comparable with the previous US survey (Correll et al., 2011), no specific differences were seen between the groups, except that high APP prescribers were more likely to be attending clinicians, rather than residents. This is consistent with the US survey, which found that high reported APP use was associated with being an attending (76.5% vs. 26.1%, p=0.0009) and having a longer practice in psychiatry (20.8+/−13.8 years vs. 9.5+/−11.3 years, p=0.0046) (Correll et al., 2011). One potential explanation may be that attending clinicians treat more severely ill patients, or that they are more likely to have inherited patients from the time of rapid neuroleptization in the 1970s when even more APP was used in Asia (Gallego et al., 2012a).

One question raised by this survey study is why the APP rate is this high in Japan. It was surprising that high and low APP prescribers shared similar levels of concern and justification toward APP, in that such attitudes did not have a significant impact on their APP prescribing behavior. Similar results were found in the US-based study (Correll et al., 2011). Moreover, despite a considerably lower reported APP rate in the US compared to that of Japan (17.0±27.0% vs. 47.7±24.7%, respectively), the psychiatrists’ general attitude toward APP was not that different between the two countries. For example, psychiatrists in both countries were “moderately” concerned about APP. Although conversion to monotherapy was successful in 28% in both countries, prescribers did not attempt conversion in 41% of cases in US and in 35% of cases in Japan. Moreover the ranking of justifications for and concerns about APP were similar, except that “lack of evidence” ranked lower in Japan as a concern about APP. It is not easy to explain considerably different reported APP rates despite such similarity. However, APP prescribing habits may reflect direct and indirect influences of current and local standard of care as well as training, and may be less determined by concepts and attitudes of the prescriber regarding APP.

Another question is whether inaccessibility to clozapine has anything to do with the high utilization of APP in Japan. Clozapine is the only antipsychotic, which has consistent evidence for efficacy in the treatment of refractory patients (Chakos et al., 2001; Kane et al., 1988), hence it is potentially understandable that APP is high in a country where clozapine is not available. However, even in settings where clozapine is available, prescribers have reported a preference toward combining antipsychotics, rather than using clozapine (Nielsen et al., 2010), and combining antipsychotics as one way of attempting to address treatment refractoriness is common practice (Correll and Gallego, in press). We attempted to examine the impact of inaccessibility to clozapine on APP among Japanese psychiatrists. In fact, failure or intolerance to clozapine treatment ranked high for justification of APP (which was a hypothetical and, thus, optional question at that time for Japanese psychiatrists). However, due to the low response rate (23%), these findings are difficult to interpret. The best way to study the potential APP-increasing effect of inaccessibility of clozapine would be to evaluate changes in APP prescription patterns a few years after the introduction of clozapine in Japan. As a side note, clozapine was only introduced in Japan in 2010, which was after the survey was conducted, and since then the initiation has still been limited to certain inpatient settings.

With regard to specific antipsychotic combinations, risperidone+levomepromazine was the most frequently prescribed co-treatment, followed by risperidone+quetiapine, and risperidone+olanzapine. It seemed that the high potency risperidone served as the main antipsychotics, whereas the lower potency antipsychotics, levomepromazine and quetiapine, served as secondary antipsychotics. This strategy is somewhat similar to the findings in the US survey and to other reports where quetiapine and clozapine were most often part of APP (Correll and Gallego, in press; Correll et al., 2007; Correll et al., 2011). Presumably, these secondary antipsychotics are used in an attempt to reduce extrapyramidal side effects (Faries et al., 2005; Ganguly et al., 2004; Jaffe and Levine, 2003; Stahl and Grady, 2004), for sleep induction, or to reduce anxiety and agitation (Chue et al., 2001; Correll et al., 2011; Potkin et al., 2002). However, again, the biggest difference to results in other countries is the lack of clozapine availability in Japan at the time of our study, and it is difficult to determine how much this influenced the individual APP prescription pattern in Japan.

The results of the study need to be interpreted in the context of limitations. First we asked psychiatrists to base their answer on their clinical practice. However, it is most likely impossible to be perfectly accurate or candid when answering the questions, such as the frequency of APP or the justifications for APP. Respondents may have underestimated the use of APP since it is discouraged in the literature, or they might have chosen some ideal reasons for justifying APP, which does not necessarily reflect their everyday decision making. Second, although we included teaching hospitals as well as non-academic, psychiatric hospitals and clinics, psychiatrists were not randomly selected. Most of the facilities that participated in the survey were located in Tokyo or other prefectures nearby. Hence, the results of the survey were not necessarily reflective of all of the regions in Japan. In addition, psychiatrists who participated in the survey are likely to be more interested in this issue, or familiar with the literature. The low return rate (40%) could have further increased this selection bias. This is an inherent difficulty of any survey, however, the large sample size (217 psychiatrists) may have somewhat minimized this bias. Lastly, some clinical characteristics, such as agitation or aggression, can have a big impact on APP, however, we did not cover these areas which can limit the interpretation of the results.

Given inconsistent efficacy results of APP and the potential for increased side effects and cost, APP should remain a last-resort treatment option after monotherapy, switching and non-antipsychotic combinations have failed (Essock et al., 2011; Fleischhacker and Uchida, 2012; Gallego et al., 2012b). There are studies that examined the impact of interventions to convert APP to antipsychotic monotherapy; from educational interventions (Baandrup et al., 2010) to more aggressive ones including active prescription monitoring and direct feedback (Hazra et al., 2011; Laska et al., 1980; Thompson et al., 2008). As passive interventions have shown to have limited efficacy, while more active interventions have a larger effect on decreasing APP (Fleischhacker and Uchida, 2012; Tani et al., in press), the results of this study are potentially helpful in informing more specific approaches, such as identifying specific target doctor populations, concerns that are underestimated, or justifications that are overestimated.

As the survey indicated that prescribing habits may be less determined by concepts and attitudes of the prescriber than might be expected, further research needs to be done to examine the impact of regulations or cultural determinants on APP. Moreover, since inaccessibility to clozapine might have contributed the high reported APP rate in Japan, APP utilization studies should be conducted that compare APP before and after clozapine introduction, and the survey should be repeated after clozapine has been widely available in a few years in order to assess potential changes in attitudes toward APP.

Acknowledgments

We thank Drs. Shintaro Nio, Akiko Abe, Mia Matsuzawa, Yuka Seo, Takuto Ishida, Minoru Inamura, Takashi Nagasawa, Hirokazu Shida, Mitsusuke Yoshida, Jo Okubo, Koichi Masuyama, Yoko Yoshinaga, Akiko Nagata, Makiko Kishimoto, Yuuta Miura, Kenji Sanada, Yuko Fujita, Akira Kubota, Hidehiro Oshibuchi, Atsushi Ikeda, Kenichi Tsunoda, Akira Kishimoto, Tokuro Sugihara, Akiko Goto, and Mihoko Tokushige for distributing/collecting the survey, and giving us the feedback for the survey design and strategy.

Funding:

Supported in part by The Zucker Hillside Hospital Advanced Center for Intervention and Services Research for the Study of Schizophrenia (MH090590) from the National Institute of Mental Health, Bethesda, MD. The sponsor had no influence on the design, data acquisition, data analysis, data interpretation or writing of the report.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Financial Disclosures:

Dr. Kishimoto has received consultant fees from Otsuka, Pfizer, Dainippon Sumitomo, and speaker’s honoraria from Banyu, Eli Lilly, Dainippon Sumitomo, Janssen, Novartis, Otsuka and Pfizer. He has received grant support from the Byoutaitaisyakenkyukai Fellowship (Fellowship of Astellas Foundation of Research on Metabolic Disorders) and Eli Lilly Fellowship for Clinical Psychopharmacology.

Dr. Watanabe has recerived grants, or consultant fees from Dainippon Sumitomo Pharrma, Eli Lilly, GlaxoSmithKline, Mochida Pharmaceutical, Otsuka Pharmaceutical, Pfizer, and received speaker’s honoraria from Astellas Pharma, Dainippon Sumitomo Pharma, Eli Lilly. GlaxoSmithKline, Janssen Pharmaceutical, Meiji Pharma, Mochida Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Shionogi, Yoshitomi Yakuhin.

Dr. Uchida has received grants from Pfizer, Astellas Pharmaceutical, Eisai, Otsuka Pharmaceutical, GlaxoSmithKline, Shiohogi, and Dainippon-Sumitomo Pharma, Eli Lilly, Mochida Pharmaceutical, Meiji-Seika Pharma, Janssen Pharmaceutical, and Yoshitomi Yakuhin and speaker’s honoraria from Otsuka Pharmaceutical, Janssen Pharmaceutical, Novartis Pharma, Eli Lilly, Shionogi, GlaxoSmithKline, Yoshitomi Yakuhin, Dainippon-Sumitomo Pharma, and Janssen Pharmaceutical within the past 2 years.

Dr. Mimura has received grants, consultant fees and/or speaker’s honoraria from Asahi Kasei, Astellas, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Meiji, Mochida, Novartis, Otsuka, Pfizer, Shionogi, and Yoshitomi.

Dr. Kane has been a consultant to Alkermes, Amgen, Astra-Zeneca, Janssen, Pfizer, Eli Lilly, Bristol-Myers Squibb, Dainippon Sumitomo/Sepracor/Sunovion, Johnson & Johnson, Otsuka, Pierre Fabre. Vanda, Proteus, Takeda, Targacept, IntraCellular Therapies, Merck, Lundbeck, Novartis, Roche, Rules Based Medicine, Sunovion and has received honoraria for lectures from Otsuka, Eli Lilly, Esai, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck and Janssen. He is a shareholder of MedAvante. He has received grant support from The National Institute of Mental Health.

Dr. Correll has been a consultant and/or advisor to or has received honoraria from: Actelion, Alexza; American Academy of Child and Adolescent Psychiatry, AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Gerson Lehrman Group, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, National Institute of Mental Health, Novartis, Ortho-McNeill/Janssen/J&J, Otsuka, Pfizer, ProPhase, Sunovion, Takeda and Teva. He has received grant support from BMS, Feinstein Institute for Medical Research, Janssen/J&J, National Institute of Mental Health (NIMH), National Alliance for Research in Schizophrenia and Depression (NARSAD), and Otsuka.

Contributors:

TK and WK contributed to designing the study, translation of the survey, collecting data, data analysis, and writing the report. HU contributed to data analysis and writing the report. MM and JK contributed to writing the report. CC contributed to designing the study, data analysis, and writing the report.

Reference

  1. Argo TR, Crismon ML, Miller AL, Moore TA, Bendele SD, Suehs B. Texas Medication Algorithm Project Procedural Manual: Schizophrenia Algorithm. Texas Department of State Health Services; Austin, Texas: 2008. [Google Scholar]
  2. Baandrup L, Allerup P, Lublin H, Nordentoft M, Peacock L, Glenthoj B. Evaluation of a multifaceted intervention to limit excessive antipsychotic co-prescribing in schizophrenia out-patients. Acta Psychiatr Scand. 2010;122:367–374. doi: 10.1111/j.1600-0447.2010.01553.x. [DOI] [PubMed] [Google Scholar]
  3. Baandrup L, Sørensen J, Lublin H, Nordentoft M, Glenthoj B. Association of antipsychotic polypharmacy with health service cost: a register-based cost analysis. Eur J Health Econ. 2012;13:355–363. doi: 10.1007/s10198-011-0308-0. [DOI] [PubMed] [Google Scholar]
  4. Broekema WJ, de Groot IW, van Harten PN. Simultaneous prescribing of atypical antipsychotics, conventional antipsychotics and anticholinergics-a European study. Pharm World Sci. 2007;29:126–130. doi: 10.1007/s11096-006-9063-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brunot A, Lachaux B, Sontag H, Casadebaig F, Philippe A, Rouillon F, Cléry-Melin P, Hergueta T, Llorca PM, Moreaudefarges T, Guillon P, Lebrun T. [Pharmaco-epidemiological study on antipsychotic drug prescription in French Psychiatry: Patient characteristics, antipsychotic treatment, and care management for schizophrenia] Encephale. 2002;28:129–138. [PubMed] [Google Scholar]
  6. Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA, Himelhoch S, Fang B, Peterson E, Aquino PR, Keller W. The 2009 Schizophrenia PORT Psychopharmacological Treatment Recommendations and Summary Statements. Schizophrenia Bulletin. 2010;36:71–93. doi: 10.1093/schbul/sbp116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Canadian Psychiatric Association Clinical practice guidelines. Treatment of schizophrenia. Can J Psychiatry. 2005;50:7S–57S. [PubMed] [Google Scholar]
  8. Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry. 2001;158:518–526. doi: 10.1176/appi.ajp.158.4.518. [DOI] [PubMed] [Google Scholar]
  9. Chue P, Welch R, Snaterse M. Combination risperidone and quetiapine therapy in refractory schizophrenia. Can J Psychiatry. 2001;46:86–87. [PubMed] [Google Scholar]
  10. Clark RE, Bartels SJ, Mellman TA, Peacock WJ. Recent trends in antipsychotic combination therapy of schizophrenia and schizoaffective disorder: implications for state mental health policy. Schizophr Bull. 2002;28:75–84. doi: 10.1093/oxfordjournals.schbul.a006928. [DOI] [PubMed] [Google Scholar]
  11. Correll C, Gallego J. Antipsychotic polypharmacy: A comprehensive evaluation of relevant correlates of a long-standing clinical practice. Psychiatr Clin N Am. doi: 10.1016/j.psc.2012.06.007. in press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Correll CU, Frederickson AM, Kane JM, Manu P. Does antipsychotic polypharmacy increase the risk for metabolic syndrome? Schizophr Res. 2007;89:91–100. doi: 10.1016/j.schres.2006.08.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Correll CU, Rummel-Kluge C, Corves C, Kane JM, Leucht S. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull. 2009;35:443–457. doi: 10.1093/schbul/sbn018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Correll CU, Shaikh L, Gallego JA, Nachbar J, Olshanskiy V, Kishimoto T, Kane JM. Antipsychotic polypharmacy: A survey study of prescriber attitudes, knowledge and behavior. Schizophrenia research. 2011;131:58–62. doi: 10.1016/j.schres.2011.02.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Essock SM, Schooler NR, Stroup TS, McEvoy JP, Rojas I, Jackson C, Covell NH, Network ST. Effectiveness of switching from antipsychotic polypharmacy to monotherapy. Am J Psychiatry. 2011;168:702–708. doi: 10.1176/appi.ajp.2011.10060908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Falkai P, Wobrock T, Lieberman J, Glenthoj B, Gattaz WF, Moller HJ, Guideli WTFT. World Federation of Societies of Biological Psychiatry (WFSBP) - Guidelines for biological treatment of schizophrenia, part 1: Acute treatment of schizophrenia. World Journal of Biological Psychiatry. 2005;6:132–191. doi: 10.1080/15622970510030090. [DOI] [PubMed] [Google Scholar]
  17. Faries D, Ascher-Svanum H, Zhu B, Correll C, Kane J. Antipsychotic monotherapy and polypharmacy in the naturalistic treatment of schizophrenia with atypical antipsychotics. BMC Psychiatry. 2005;5:26. doi: 10.1186/1471-244X-5-26. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fleischhacker WW, Uchida H. Critical review of antipsychotic polypharmacy in the treatment of schizophrenia. Int J Neuropsychopharmacol. 2012:1–11. doi: 10.1017/S1461145712000399. [DOI] [PubMed] [Google Scholar]
  19. Fourrier A, Gasquet I, Allicar MP, Bouhassira M, Lépine JP, Bégaud B. Patterns of neuroleptic drug prescription: a national cross-sectional survey of a random sample of French psychiatrists. Br J Clin Pharmacol. 2000;49:80–86. doi: 10.1046/j.1365-2125.2000.00108.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Gallego JA, Bonetti J, Zhang J, Kane JM, Correll CU. Prevalence and correlates of antipsychotic polypharmacy: A systematic review and meta-regression of global and regional trends from the 1970s to 2009. Schizophr Res. 2012a;138:18–28. doi: 10.1016/j.schres.2012.03.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Gallego JA, Nielsen J, De Hert M, Kane JM, Correll CU. Safety and tolerability of antipsychotic polypharmacy. Expert Opin Drug Saf. 2012b;11:527–542. doi: 10.1517/14740338.2012.683523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ganguly R, Kotzan JA, Miller LS, Kennedy K, Martin BC. Prevalence, trends, and factors associated with antipsychotic polypharmacy among Medicaid-eligible schizophrenia patients, 1998-2000. J Clin Psychiatry. 2004;65:1377–1388. doi: 10.4088/jcp.v65n1013. [DOI] [PubMed] [Google Scholar]
  23. Hazra M, Uchida H, Sproule B, Remington G, Suzuki T, Mamo DC. Impact of feedback from pharmacists in reducing antipsychotic polypharmacy in schizophrenia. Psychiatry Clin Neurosci. 2011;65:676–678. doi: 10.1111/j.1440-1819.2011.02280.x. [DOI] [PubMed] [Google Scholar]
  24. Ito C, Kubota Y, Sato M. A prospective survey on drug choice for prescriptions for admitted patients with schizophrenia. Psychiatry Clin Neurosci. 1999;53:S35–40. Suppl. [PubMed] [Google Scholar]
  25. Ito H, Koyama A, Higuchi T. Polypharmacy and excessive dosing: psychiatrists’ perceptions of antipsychotic drug prescription. Br J Psychiatry. 2005;187:243–247. doi: 10.1192/bjp.187.3.243. [DOI] [PubMed] [Google Scholar]
  26. Jaffe AB, Levine J. Antipsychotic medication coprescribing in a large state hospital system. Pharmacoepidemiol Drug Saf. 2003;12:41–48. doi: 10.1002/pds.783. [DOI] [PubMed] [Google Scholar]
  27. Joukamaa M, Heliövaara M, Knekt P, Aromaa A, Raitasalo R, Lehtinen V. Schizophrenia, neuroleptic medication and mortality. Br J Psychiatry. 2006;188:122–127. doi: 10.1192/bjp.188.2.122. [DOI] [PubMed] [Google Scholar]
  28. Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988;45:789–796. doi: 10.1001/archpsyc.1988.01800330013001. [DOI] [PubMed] [Google Scholar]
  29. Kreyenbuhl J, Valenstein M, McCarthy JF, Ganoczy D, Blow FC. Long-term combination antipsychotic treatment in VA patients with schizophrenia. Schizophr Res. 2006;84:90–99. doi: 10.1016/j.schres.2006.02.023. [DOI] [PubMed] [Google Scholar]
  30. Laska E, Siegel C, Simpson G. Automated review system for orders of psychotropic drugs. Arch Gen Psychiatry. 1980;37:824–827. doi: 10.1001/archpsyc.1980.01780200102013. [DOI] [PubMed] [Google Scholar]
  31. McGorry P, Killackey E, Lambert T, Lambert M, Jackson H, Codyre D, James N, Pantelis C, Pirkis J, Jones P, Durie MA, McGrath J, McGlashan T, Malla A, Farhall J, Hermann H, Hocking B, Royal Australian New Zealand, C. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of schizophrenia and related disorders. Australian and New Zealand Journal of Psychiatry. 2005;39:1–30. doi: 10.1080/j.1440-1614.2005.01516.x. [DOI] [PubMed] [Google Scholar]
  32. National Collaborating Centre for Mental Health . The British Psychological Society and The Royal College of Psychiatrists. Leicester, London: 2010. The NICE Guidelines on Core Interventions in the Treatment and Management of Schizophrenia in Primary and Secondary Care (update edition) [Google Scholar]
  33. Nielsen J, Dahm M, Lublin H, Taylor D. Psychiatrists’ attitude towards and knowledge of clozapine treatment. J Psychopharmacol. 2010;24:965–971. doi: 10.1177/0269881108100320. [DOI] [PubMed] [Google Scholar]
  34. Potkin SG, Thyrum PT, Alva G, Bera R, Yeh C, Arvanitis LA. The safety and pharmacokinetics of quetiapine when coadministered with haloperidol, risperidone, or thioridazine. J Clin Psychopharmacol. 2002;22:121–130. doi: 10.1097/00004714-200204000-00004. [DOI] [PubMed] [Google Scholar]
  35. Procyshyn RM, Kennedy NB, Tse G, Thompson B. Antipsychotic polypharmacy: a survey of discharge prescriptions from a tertiary care psychiatric institution. Can J Psychiatry. 2001;46:334–339. doi: 10.1177/070674370104600404. [DOI] [PubMed] [Google Scholar]
  36. Sernyak MJ, Rosenheck R. Clinicians’ reasons for antipsychotic coprescribing. J Clin Psychiatry. 2004;65:1597–1600. doi: 10.4088/jcp.v65n1203. [DOI] [PubMed] [Google Scholar]
  37. Sim K, Su A, Chan YH, Shinfuku N, Kua EH, Tan CH. Clinical correlates of antipsychotic polytherapy in patients with schizophrenia in Singapore. Psychiatry Clin Neurosci. 2004;58:324–329. doi: 10.1111/j.1440-1819.2004.01239.x. [DOI] [PubMed] [Google Scholar]
  38. Stahl SM, Grady MM. A critical review of atypical antipsychotic utilization: comparing monotherapy with polypharmacy and augmentation. Curr Med Chem. 2004;11:313–327. doi: 10.2174/0929867043456070. [DOI] [PubMed] [Google Scholar]
  39. Tani H, Uchida H, Suzuki T, Fujii Y, Mimura M. Intervention to reduce antipsychotic polypharmacy: A systematic review. Schizophrenia Research. doi: 10.1016/j.schres.2012.10.015. in press. [DOI] [PubMed] [Google Scholar]
  40. Tapp A, Wood AE, Secrest L, Erdmann J, Cubberley L, Kilzieh N. Combination antipsychotic therapy in clinical practice. Psychiatr Serv. 2003;54:55–59. doi: 10.1176/appi.ps.54.1.55. [DOI] [PubMed] [Google Scholar]
  41. Thompson A, Sullivan SA, Barley M, Strange SO, Moore L, Rogers P, Sipos A, Harrison G. The DEBIT trial: an intervention to reduce antipsychotic polypharmacy prescribing in adult psychiatry wards - a cluster randomized controlled trial. Psychol Med. 2008;38:705–715. doi: 10.1017/S003329170700147X. [DOI] [PubMed] [Google Scholar]
  42. Wang PS, West JC, Tanielian T, Pincus HA. Recent patterns and predictors of antipsychotic medication regimens used to treat schizophrenia and other psychotic disorders. Schizophr Bull. 2000;26:451–457. doi: 10.1093/oxfordjournals.schbul.a033465. [DOI] [PubMed] [Google Scholar]
  43. Yoshio T, Inada T, Uno J, Miwa T, Kitagawa K, Miyahara Y, Umeda K, Kato T, Inagaki A, Nabeshima T. Prescription profiles for pharmacological treatment of Japanese inpatients with schizophrenia: comparison between 2007 and 2009. Hum Psychopharmacol. 2012;27:70–75. doi: 10.1002/hup.1272. [DOI] [PubMed] [Google Scholar]

RESOURCES