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Interventions to reduce antipsychotic polypharmacy: A systematic review

Schizophrenia Research, 1, 143, pages 215 - 220

Abstract

Background

It still remains unclear as to how to counteract antipsychotic polypharmacy that remains controversial but common. The objective of this study was to synthesize the clinical evidence to reduce antipsychotic polypharmacy (i.e. use of multiple antipsychotics) in schizophrenia.

Methods

A literature search was performed to identify clinical trials that attempted to reduce antipsychotic polypharmacy in patients with schizophrenia by any form of systematic intervention using PubMed as well as MEDLINE, EMBASE, and PsycINFO (last search: June 2012). The search terms included “antipsychotics” and “polypharmacy”. Cross-referencing was also performed.

Results

The literature search identified 17 studies. Only 3 studies (1 randomized controlled trial and 2 open-label trials) were found that systematically switched antipsychotic polypharmacy to monotherapy. In two of them, more than two thirds of the subjects successfully completed the switch (40/58, 69.0%; 34/44, and 77.3%, respectively) while less than half the subjects tolerated it in the other study (6/14 and 42.9%) although the sample size was very small. On the other hand, 14 studies that examined impacts of interventions have physicians refrain from antipsychotic polypharmacy. While a modest intervention with educational approach alone was effective in three of the five articles, a more assertive intervention that directly cautioned physicians on the use of polypharmacy was effective in 10 of 12 articles.

Conclusion

The literature search revealed the paucity of the data. Careful switching from polypharmacy to monotherapy seems feasible in a majority of patients with schizophrenia. Assertive interventions, rather than passive educational approaches alone, appear more effective in reducing antipsychotic polypharmacy.

Keywords: Antipsychotic, Intervention, Polypharmacy, Schizophrenia.

1. Introduction

Antipsychotic polypharmacy (i.e. concurrent use of more than one antipsychotic drug) has been prevailing in real-world clinical settings with prevalence rates ranging from 4% up to 70%, depending on the treatment setting and the patient population (Paton et al, 2003, Ito et al, 2005, Stahl and Grady, 2006, Xiang et al, 2007, Koen et al, 2008, Procyshyn et al, 2010, Santone et al, 2011, and Tsutsumi et al, 2011). Furthermore, the use of antipsychotic polypharmacy appears to have been increasing in some countries, including the US and Denmark (Gilmer et al, 2007 and Nielsen et al, 2010) although it has been decreasing in certain countries/regions such as Japan and Hong Kong (Tsutsumi et al, 2011, Xiang et al, 2012, and Yoshio, 2012). The evidence on the effectiveness of antipsychotic polypharmacy from clinical trials has been inconsistent (Cipriani et al, 2009 and Correll et al, 2009), but this therapy is clearly associated with a variety of unwanted effects, including increases in adverse events (Ray et al, 2009, Uchida et al, 2009, and Misawa et al, 2011), unnecessary economic burden ( Stahl and Grady, 2006 ), and low adherence to treatment (Benner et al, 2009 and Bailey and Kodack, 2011). In fact, all available clinical guidelines for schizophrenia recommend antipsychotic monotherapy and suggest the usage of antipsychotic polypharmacy as a last resort (Canadian Psychiatric Association, 2005, Royal Australian and New Zealand College of Psychiatrists, 2005, Falkai et al, 2006, Argo et al, 2008, Buchanan et al, 2010, and National Collaborating Centre for Mental Health, 2010). Although the pros and cons of antipsychotic polypharmacy have frequently been discussed both from theoretical and real-world perspectives, the evidence is still scarce as to how to deal with patients who have already received such treatment. This issue is critically important in clinical practice, given the high and likely increasing prevalence rates of antipsychotic polypharmacy in patients with schizophrenia.

A systematic review of currently available publications will improve our understanding of how to counteract this common but controversial practice and also elucidate potentially effective strategies to deal with this therapy. The objective of this study was to synthesize the evidence on trials that attempted to reduce antipsychotic polypharmacy, defined as simultaneous use of multiple antipsychotic drugs, in a systematic fashion for patients with schizophrenia.

2. Methods

A comprehensive literature search was performed to identify studies that attempted to reduce antipsychotic polypharmacy in patients with schizophrenia as a main interest by any form of systematic interventions. The following search terms were used in this systematic literature search, using PubMed, Ovid MEDLINE(R), EMBASE and PsycINFO (last search: June 2012): (antipsychotic or antipsychotics or neuroleptic or neuroleptics) AND (polypharmacy or polytherapy or combination). Only articles written in English and Japanese were included. Cross-referencing of the identified articles was also performed. Literature search was conducted independently by two of the authors (H.T. and T.S.). Eligible interventions were critically appraised for their study design and summarized accordingly.

3. Results

A total of 17 studies were identified through the literature search and critically appraised in this review. Of the 17 studies, 3 were clinical trials that systematically switched antipsychotic polypharmacy to monotherapy and 14 were studies that examined impacts of interventions to have physicians refrain from antipsychotic polypharmacy.

3.1. Direct interventions to change regimens

The literature search identified only 3 clinical trials that systematically converted polypharmacy to monotherapy: 1 randomized controlled trial (RCT) and 2 open-label trials.

Godleski et al. (1989) conducted a 12-month open-label trial in which one of two simultaneously used antipsychotics was discontinued in 14 chronic inpatients with mixed diagnoses (12 with schizophrenia and 2 with schizoaffective disorder) ( Godleski et al., 1989 ). This study targeted difficult-to-treat patients who had a duration of illness of more than 10 years with a current hospitalization lasting at least 1 year and had been refractory to five antipsychotic medications as well as to lithium and carbamazepine. At baseline, all patients were treated with two FGAs, and one of them was tapered by roughly 10% every 1 to 2 weeks. The choice of which antipsychotic to continue was determined considering of larger relative doses, previous efficacy, patient preference and route of administration. The results showed that the conversion to antipsychotic monotherapy was successful in 6 of 14 patients (42.9%) (chlorpromazine equivalent dose, from 2533 mg/day to 1883 mg/day) while the rest of 8 patients experienced a clinical worsening and therefore did not complete the conversion to antipsychotic monotherapy (chlorpromazine equivalent dose, from 3463 mg/day to 2494 mg/day).

Suzuki et al. (2004) conducted a pragmatic open-label trial to convert antipsychotic polypharmacy to monotherapy with a main antipsychotic drug in 47 patients with chronic schizophrenia in a cross-tapered fashion ( Suzuki et al., 2004 ). A main antipsychotic was defined as the drug that accounted for a majority of the daily chlorpromazine equivalent dose in each subject. Of 44 patients for whom evaluation was feasible, 24 (54.5%) remained stable, 10 (22.7%) showed improvement, and 10 patients (22.7%) worsened; this means 34/44 (77.3%) successfully completed the switch to antipsychotic monotherapy. Scores in the Global Assessment of Functioning (GAF) and the Clinical Global Impression (CGI) remained unchanged. The 10 patients who experienced clinical worsening were managed by the reintroduction of their previous antipsychotics. This study had several limitations. Only first generation antipsychotics (FGAs) were studied with an exception of risperidone because of the availability at the time of the study. The assessment was confined to global impression and functioning, and the study was open-label.

Essock et al. (2011) reported a six-month RCT to compare outcomes between staying on antipsychotic polypharmacy and switching to monotherapy in 127 outpatients with schizophrenia who were receiving multiple antipsychotic drugs ( Essock et al., 2011 ). Each participant and physician decided together which of the two antipsychotics to discontinue in the switching group. Time to all cause treatment discontinuation was shorter in the monotherapy group than the polypharmacy group. Moreover, while only 8 of the 56 patients (14.3%) in the polypharmacy prematurely withdrew from the study, 18 of the 58 patients (31.0%) who were assigned to monotherapy did so. However, from a different viewpoint, approximately two-thirds (69.0%) of the patients assigned to the monotherapy group were successfully switched to antipsychotic monotherapy. Moreover, weight control was better with monotherapy and no significant difference was observed between the two groups with respect to psychiatric symptom change or incidence of hospitalization.

3.2. Interventions to have physicians refrain from antipsychotic polypharmacy

We have found that interventions used in previous trials can be, albeit somewhat arbitrarily, sorted into the following two categories: (1) modest interventions that mainly include one-way, passive dissemination of knowledge by providing educational seminars and lectures on the demerits of antipsychotic polypharmacy and (2) assertive interventions in which physicians are encouraged to refrain from the use of polypharmacy by more active forms of communication such as face-to-face feedback, letters and phone calls.

3.2.1. RCT

The literature search identified only three RCTs that compared effectiveness between modest and assertive interventions in reducing antipsychotic polypharmacy ( Table 1 ).

Table 1 Randomized controlled trials that compared modest vs. assertive interventions to have physicians refrain from antipsychotic polypharmacy (AP).

Author

(Year)
Intervention type Population AP, N/(%) Duration Intervention Effectiveness
Baseline Post-intervention
Owen et al. (2008) Modest Schizophrenia, acute exacerbation 291

(11%)
N/A

(10%)
6 M Implementing antipsychotic management of VA schizophrenia guidelines No
Assertive   291

(14%)
N/A

(23%)
  Promotion of provider guideline adherence and patient compliance by a trained nurse No
Thompson et al. (2008) Modest Patients in adult psychiatric wards 71/204

(34.8%)
82/220

(41.8%)
5 M Dissemination of guidelines including the National Institute for Clinical Excellence (NICE) to doctors and nurses No
Assertive   129/270

(47.8%)
105/260

(40.4%)
  An educational/CBT workbook, an educational visit to consultants, and a reminder system on medical charts Yes
Baandrup et al. (2010) Control Schizophrenia 241/351

(68.7%)
234/386

(60.6%)
1Y N/A No
Assertive   159/232

(68.5%)
155/216

(71.8%)
  1 day of didactic lectures, six 3-hour educational outreach visits, electronic automatic reminder system No

N/A, not available; Y, year; M, month.

Owen et al. (2008) compared the effectiveness between an assertive multi-component strategy in which a trained nurse promoted adherence to treatment guidelines and a modest basic educational implementation strategy that represented usual care in two Veterans Affairs (VA) centers in the US ( Owen et al., 2008 ). 291 participants with acute exacerbation of schizophrenia were enrolled and assessed at baseline and six months after the intervention. Both strategies failed to reduce rates of the patients who were prescribed antipsychotic polypharmacy of a FGA plus a second generation antipsychotic (SGA) at the endpoint (14% to 23% in the basic intervention group and 11% to 10% in the enhanced group). Thus, the enhanced strategy did not increase guideline-recommended switching to monotherapy, which underscores the challenges of changing physicians’ prescribing behaviors.

Thompson et al. (2008) conducted a five-month pragmatic cluster RCT to investigate the effectiveness of an assertive multi-faceted intervention in 4 trusts with 19 adult acute psychiatric units in England (the DEBIT trial) ( Thompson et al., 2008 ). The multi-faceted intervention comprised of an educational/cognitive behavioral workbook, an educational visit to consultants and a reminder system on medical charts. This five-month intervention resulted in a significantly lower prevalence of antipsychotic polypharmacy at the endpoint (47.8% to 40.4%), compared with guideline dissemination alone (34.8% to 41.8%) (adjusted odds ratio: 0.43, 95% confidence interval: 0.21–0.90, p = 0.028). However, the effect size was relatively modest, and there was a considerable between-unit variation in the rates of polypharmacy. Therefore, the authors emphasized the importance of local political and cultural issues in the prescribing process.

In a one-year controlled quasi-experimental study, Baandrup et al. (2010) evaluated the effect of an assertive multifaceted educational intervention on the frequency of antipsychotic polypharmacy in outpatients with schizophrenia in two municipalities in Denmark ( Baandrup et al., 2010 ). The intervention consisted of one-day of didactic lectures, and six three-hour educational outreach visits. In addition, a warning in the electronic drug prescribing system was implemented, which popped up every time antipsychotic polypharmacy was about to be prescribed. However, these interventions failed to show any significant effectiveness in reducing antipsychotic polypharmacy, compared to the control group; rather, there was a trend being counterproductive as there was an increase of polypharmacy in the intervention group (68.5% to 71.8% in the intervention group; 68.7% to 60.6% in the control group, p = 0.07).

3.2.2. Modest interventions without control group

The literature search identified three trials that investigated modest interventions without any control group ( Table 2 ).

Table 2 Open-label one-group trials that evaluated modest interventions to have physicians refrain from antipsychotic polypharmacy (AP).

Author

(Year)
Population AP, N/(%) Duration Intervention Effectiveness
Baseline Post-intervention  
Schroeder et al. (1979) Chronic schizophrenia 3279

(N/A)
2987

(N/A) a
N/A Dissemination of previous survey feedback, a series of articles and videotapes on recommendations for psychotherapeutic drugs Yes
Chong et al. (2006) First episode psychosis 15/68

(22.7%)
20/415

(4.8%)
N/A Implementation of a treatment algorithm in early psychosis intervention programme (EPIP) Yes
Goren et al. (2010) Psychosis 132/389

(33.9%)
44/202

(21.8%)
1Y Four educational seminars to psychiatrists and day lectures to the nursing staff Yes

a The prevalence rate of AP was reduced by 4%.

N/A, not available; Y, year; M, month.

Schroeder et al. (1979) evaluated educational programs that consisted of the dissemination of articles and videotapes on recommendations on the use of psychotropic drugs for the treatment of schizophrenia in 42 VA hospitals in the US ( Schroeder et al., 1979 ). As a result, the use of polypharmacy significantly decreased by more than 4% although detailed information on study duration or baseline percentage of antipsychotic polypharmacy was not available. Chong et al. (2006) showed a significant reduction in the rate of antipsychotic polypharmacy for patients with first-episode psychosis in the Institute of Mental Health in Singapore who were enrolled into an Early Psychosis Intervention Programme (EPIP) that included implementation of a treatment algorithm ( Chong et al., 2006 ). Patients who were provided this program less frequently received antipsychotic polypharmacy, compared with a historical control group (pre-EPIP) (4.8% vs. 22.7%). Goren et al. (2010) conducted a two-step quality improvement program in two hospitals of Cambridge Health Alliance in the US and found that the percentage of polypharmacy declined from 33.9% at baseline to 21.8% after delivery of the educational modules, and to 12.2% after audit feedback ( Goren et al., 2010 ).

3.2.3. Assertive interventions without control group

There have been eight one-group trials that evaluated assertive intervention strategies; of these, all trials showed favorable results ( Table 3 ).

Table 3 Open-label one-group trials that evaluated assertive interventions to have physicians refrain from antipsychotic polypharmacy (AP).

Author

(Year)
Population AP, N / (%) Duration Intervention Effectiveness
Baseline Post-intervention
Barton (1978) Patients in department of mental health who were receiving > 4 psychotropics 9000

(1.7%)
N/A

(0.4%)
2.5Y Delivery of computer generated information about specific patients who had been prescribed more than four psychotropic drugs Yes
Laska et al. (1980) Patients in psychiatric center 1800

(11%)
N/A

(0.9%)
2.8Y Reviewing drug orders and notifying clinicians exceptions to clinical guidelines with computerized drug review system Yes
Ungvari et al. (1997) Schizophrenia 86/158

(54.3%)
54/158

(34.2%)
2Y Drug history evaluation, drawing up a treatment plan during weekly multidisciplinary meetings by the consultant psychiatrist, case conference, lectures and videos, and drug consumption lists to notify cost-effectiveness Yes
Patrick et al. (2006) Patients in psychiatric hospital 197/464

(42%)
127/386

(31%)
1Y The chief asked psychiatrists to reduce antipsychotic polypharmacy by at least 10% and compare physician's order forms with data of anonymous peers Yes
Constantine et al. (2010) Schizophrenia 4912/26063

(18.8%)
3695/22402

(16.5%)
4Y Delivery of a series of letters and peer to peer telephone consultations to follow guidelines Yes
Goren et al. (2010) Psychosis 132/389

(33.9%)
18/147

(12.2%)
2Y Monthly prescriber-specific audit feedback provided in paper form and the chief of service reviewed audit feedback individually Yes
Finnerty et al. (2011) Schizophrenia 4227

(1.69%)
N/A

(0.92%)
5Y Implementation of the PSYCKES, director approval policy to prescribe more than two antipsychotics, hospital leaders received feedback from the office Yes
Hazra et al. (2011) Schizophrenia 118/648

(18.3%)
51/778

(6.6%)
2Y Active feedback by the pharmacist to the prescribers of AP as well as educational seminars Yes
Robst (2012) Schizophrenia/

Psychosis
65304 (Monthly observations)

(14.0%)
N/A

(12.5%)
6 M Implementation of Prepaid Mental Health Plans (PMHPs). Yes

N/A, not available; Y, year; M, month; PSYCKES, Psychiatric Services Clinical Knowledge Enhancement System.

Barton (1978) evaluated effects of computer feedback on the use of polypharmacy in the Department of Mental Health (DMH) institutions in the US; in this study, clinicians received regular, computer generated information on their patients who had been prescribed more than four psychotropic drugs ( Barton, 1978 ). Following a 2.5-year intervention, the rate of use of more than 4 psychotropic drugs decreased from 1.7% to 0.4% although this study did not solely focus on antipsychotic polypharmacy. In 1980, Laska et al. reported on a computerized drug-review system which notified clinicians of orders that were considered exceptions to clinical guidelines in a New York State Psychiatric Center ( Laska et al., 1980 ). The result demonstrated a substantial reduction in the rate of polypharmacy from 11% to 0.9% after the implementation of the system. Ungvari et al. (1997) evaluated a systematic education program that included drug reviews, case conferences, lectures and videotapes and promoting awareness of cost-effectiveness in the pharmacotherapy of schizophrenia. Two years later, significant reduction was found in the percentage of patients who were concurrently receiving multiple antipsychotics (54.3% to 34.2%) ( Ungvari et al., 1997 ).

Patrick et al. (2006) reported a performance improvement initiative in a state psychiatric hospital in the US; after baseline data were collected, the chief of psychiatry section met with each psychiatrist to compare their prescribing data with anonymous peers and asked all psychiatrists to decrease antipsychotic polypharmacy by at least 10%. As a result, antipsychotic polypharmacy significantly dropped from 42.5% (197/464) in November 2001 to 31.1% (127/408) in August 2002, which indicated that the focused attention of leadership resulted in a significant reduction of antipsychotic polypharmacy. In Florida's Medicaid program, Constantine et al. (2010) evaluated a statewide quality improvement program; in this program, physicians who frequently wrote prescriptions that were inconsistent with the guidelines received letters that identified the patients associated with such practice and asked the physicians to review the guidelines and change regimens as appropriate. Furthermore, physicians who kept using antipsychotic polypharmacy after multiple mailing interventions were identified and targeted for peer to peer telephone consultation. This somewhat aggressive intervention resulted in a reduction of the rate of antipsychotic polypharmacy from 18.8% (4912/26063) to 16.5% (3695/22402) over a four-year period. Finnerty et al. (2011) conducted a series of interventions that consisted of the implementation of a web-based application as well as a policy requiring approval by the medical director to prescribe more than two antipsychotics in the New York State Office of Mental Health network of psychiatric hospitals. Following the intervention, polypharmacy significantly decreased from 16.9 to 9.7 inpatients per 1000. Similarly, in a tertiary psychiatric center in Toronto, Hazra et al. (2011) reported that active feedback, using phone calls, by the pharmacist to the prescribers who utilized antipsychotic polypharmacy reduced the prevalence of antipsychotic polypharmacy from 18.3% to 6.6% in two years. Furthermore, the prevalence of three antipsychotic combinations was decreased from 5.3% to 0.0% in this single site study. Robst (2012) reported impacts of Prepaid Mental Health Plans (PMHPs) on the prescription drug utilization among Medicaid recipients in Florida, the US. After the implementation of this prepaid system, the prevalence of antipsychotic polypharmacy declined from 14.0% to 12.5% (p < 0.001) over a 6-month period.

4. Discussion

The aim of this work was to systematically review previous trials that attempted to reduce antipsychotic polypharmacy in patients with schizophrenia. First of all, the literature search clearly revealed a paucity of data on this topic, which should be noted when the data are interpreted. In fact, there have been only three clinical trials that systematically converted polypharmacy to monotherapy. Moreover, only three RCTs evaluated interventions to actively alert physicians for prescribing two or more antipsychotics at the same time. Second, the available evidence appears to suggest that switching from polypharmacy to monotherapy is feasible in a majority of patients with schizophrenia. Moreover, assertive interventions, rather than educational approaches alone, appear more effective in reducing antipsychotic polypharmacy although the data on direct comparison have still been scarce.

Only 3 studies (1 randomized controlled trial and 2 open-label trials) were found that systematically switched antipsychotic polypharmacy to monotherapy (Godleski et al, 1989, Suzuki et al, 2004, and Essock et al, 2011). In two of them, approximately two thirds of the subjects successfully completed the switch in spite of different study design and population studied (Suzuki et al, 2004 and Essock et al, 2011) while only less than half of the subjects tolerated it in the other much smaller and older study that targeted treatment-resistant patients (N = 14) ( Godleski et al., 1989 ). It should be noted that unfavorable results in the study by Godleski et al. may not be extrapolated to general population with schizophrenia in light of the very small sample size and chronicity of the illness in the sample with a length of lifetime hospitalization of 5.1 years (mean). In addition, all subjects had suffered from the illness for greater than 10 years and had been still psychotic despite trials of at least five different antipsychotics and two other psychotropic agents. Furthermore, the dosage range in this study was as high as 750–8100 chlorpromazine equivalent mg/day, which is apparently much higher than the currently recommended one (Kane et al, 2003 and American Psychiatric Association, 2004). Thus, these issues clearly limit the interpretation of the data. The paucity of this mode of study is striking in comparison with relative abundance of the studies in which polypharmacy is tested for those who fail to respond to monotherapy. Although further investigations are clearly warranted given the paucity of the data, the currently available evidence suggests that converting antipsychotic polypharmacy to monotherapy could be a useful and reasonable treatment option in schizophrenia. Moreover, even though there is a certain risk of clinical worsening following a switch to monotherapy, clinicians always have the option to reinstate polypharmacy. Although the data are still limited, in light of the feasibility of switching patients from polypharmacy to monotherapy as well as potential benefits associated with the switch, the next challenge will be in predicting who should be maintained on polypharmacy and who can be safely switched to monotherapy ( Fleischhacker and Uchida, 2012 ).

While educational interventions that are passive have only accounted for small effects, a more active form of intervention such as directly notifying physicians by letters or phone calls appears more likely to decrease the use of antipsychotic polypharmacy although further studies are needed. Physicians may be reluctant to change their style unless they feel a certain degree of pressure from peers and bosses. For example, Correll et al. conducted a single-site interview study of prescribers at a psychiatric teaching hospital in the US and found that approximately 40% of the clinicians had not tried a switch from antipsychotic polypharmacy to monotherapy ( Correll et al., 2011 ). Similarly, Tapp et al. reviewed antipsychotic prescribing practices in the VA Department Puget Sound Health System in the US and identified 39 patients with schizophrenia who were receiving multiple antipsychotics. Of these patients, there was only one case for which the clinician intended to discontinue one of the antipsychotics ( Tapp et al., 2003 ). Thus, somewhat assertive interventions that can be perceived as fostering a ‘big-brother’- like atmosphere may be needed to change physicians’ prescribing behaviors in order to reduce antipsychotic polypharmacy. In light of a wide variety of interventions adopted in previous trials, further investigations are clearly warranted to elucidate what specific interventions are needed to result in this change.

There are several limitations to be noted in the present review. First, while we systematically investigated PubMed as well as MEDLINE, EMBASE and PsycINFO, we may still have missed some references, and only articles written in English were included in this review. Moreover, potential publication bias cannot be entirely negated as reports with positive results are more likely submitted and therefore published. Second, heterogeneous study designs and the paucity of data prevented a meta-analytic approach. Third, most of the articles included in the present review did not assess clinical outcomes, which limits interpretation of the data. Fourth, a possibility of publication bias in favor of assertive interventions cannot be entirely rejected. Fifth, the application of intervention is particularly relevant to the cultural context. The making phone calls by pharmacist or writing letters to doctors may not be optimal way to reduce polypharmacy prescriptions in Asian countries. Finally, individual motives to quit antipsychotic polypharmacy are likely to widely differ among clinicians, which have not previously been investigated. Ideally, any attempt to revise polypharmacy should be anchored on these personal motives in future investigations.

In conclusion, the literature search clearly revealed a lack of robust data on effective strategies to antipsychotic polypharmacy in the treatment of schizophrenia. Although the paucity of the data is still a concern, currently available clinical trials have shown that a general reduction of polypharmacy is possible in many types of treatment settings. Furthermore, antipsychotic polypharmacy can be reduced through changes in physicians’ prescribing habits with focused interventions rather than routine education. These preliminary conclusions have to be confirmed in well-designed trials, such as large-scale multi-site RCTs with a focus on cultural aspects, and the limited evidence clearly points to the need of further investigations on this prevailing but controversial practice.

Role of funding source

None.

Contributors

HT, HU, and TS contributed to the conception and design of the study, literature search, and the analysis. HT wrote the first draft of the manuscript. All authors contributed to the interpretation of the data and have approved the final manuscript.

Conflict of interest

Dr. Uchida has received grants from Pfizer and Dainippon-Sumitomo Pharma, and speaker's honoraria from Otsuka Pharmaceutical, Janssen Pharmaceutical, Novartis Pharma, Eli Lilly, Shionogi, GlaxoSmithKline, Yoshitomi Yakuhin, Dainippon-Sumitomo Pharma, and Janssen Pharma within the past 5 years. Dr. Suzuki has received manuscript fees or speaker's honoraria from Dainippon Sumitomo Phama, Eli Lilly and Astellas Pharma within the past 5 years. Dr. Fujii has received speaking fees from Janssen Pharmaceutica, and Eli Lilli within the past 5 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 within the past 5 years. Dr. Tani has nothing to disclose.

Acknowledgements

The authors thank Ms. Aki Endo and Ms. Ai Otani for their administrative support.

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Footnotes

a Department of Psychiatry, Yamanashi Prefectural Kita Hospital, Yamanashi, Japan

b Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan

c Geriatric Mental Health Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

d Department of Psychiatry, Inokashira Hospital, Tokyo, Japan

lowast Corresponding author at: Department of Neuropsychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. Tel.: + 81 3 5363 3829; fax: + 81 3 5379 0187.

Previous presentation: None

☆☆ Sources of financial support: None