Long-Acting Injectable Antipsychotic Treatment for Schizophrenia in Asian Population: A Scoping Review

Figures & data

Table 1 Summary of All Included Studies 

Authors and Year of Publication	Study Country or Region	Study Design	Study Period	Sample Size	LAI Group (s)	Comparator	Follow-Up	Main Outcomes	Main Findings
Adam J Savitz_2017^Citation38	Multi center	RCT	2012–2015	344	PP3M; PP1M	PP3M; PP1M	4 weeks	PANSS; CGI-S; PSP; relapse rate; AE;	PP3M is efficacious in the East Asian subgroup. Although treatment-emergent adverse events were slightly higher in the East Asian subgroup versus the global population, no new safety signals were identified.
Adam J Savitz_2019^Citation39	Multi center	RCT	2012–2015	995	PP3M; PP1M	PP3M; PP1M	4–12 weeks	PANSS; CGI-S; PSP; AE;	PP3M showed similar efficacy to PP1M in Europeans and non-Europeans, consistent with non-inferiority of PP3M to PP1M observed in overall population. Rates of AEs were higher in non-Europeans. However, weight gain was greater in non-Europeans, especially the Asian population.
Bai Hanping_2015^Citation40	Wuhan Province	RCT	2012–2014	80	PP1M	OAM-Risperidone	1 years	PSP; MSQ; relapse rate; discontinuation rate;	Long-acting paliperidone palmitate injection in the treatment of patients could improve social function and medication satisfaction, treatment compliance and remission, drug withdrawal, relapse and rehospitalization, so that it can be used in out-of-hospital long-term maintenance treatment of college students with schizophrenia safely and effectively.
Chen-Chung Liu_2013^Citation41	Taiwan region	Cohort study	2004–2008	92	LAIs; Risperidone; Flupentixol; Fluphenazine c;	Risperidone-Flupentixol-Fluphenazine-OAMs	3 years	Adherence;	Initiating LAIAs during admission for an acute psychotic episode, to a group of patients with an inadequate previous treatment response and poorer compliance, might keep their rehospitalization rates to the level of their oral antipsychotic medication treated counterparts.
Ching-Hua Lin_2020^Citation42	Taiwan region	Cohort study	2016–2018	1168	LAIs	OAMs	1 year	HCRU; discontinuation rate;	LAIs were found superior to oral antipsychotics (OAPs) in preventing rehospitalization. A continuous increase in second-generation LAI prescription rate may be due to the better side-effect profile of second-generation LAIs compared to first-generation LAIs. More studies investigating the effectiveness of LAIs in elderly patients with schizophrenia are needed in the future.
Chi-Shin Wu_2016^Citation43	Taiwan region	Cohort study	2004–2008	13,060	Clopentixol/zuclopentixol; Flupentixol; Fluphenazine; Haloperidol	LAI-Risperidone	1 year	Cost; discontinuation rate;	Patients taking the RLAI may be more effective in some but not all outcome measures; however, risperidone was also associated with higher medical costs in the healthcare setting.
Chiun-Fang Chiou_2015^Citation44	Multi center	Cohort study	NA	311	PP1M	PP1M-China-Korea-Malaysia	1.5 years	HCRU; Cost;	The results suggest that reductions in hospital utilization cost were associated with PP treatment, likely largely due to increased adherence to treatment.
Dasom Lee_2020^Citation45	Korea	Mirror-image study	2010–2017	1272	PP1M	Pre-post	8 years	HCRU; Cost;	The high prescription costs for PP may be counterbalanced by the reduced admission costs associated with its use. Economic outcomes for patients treated with LAIs should be investigated further to help healthcare decision-makers and providers to determine the value of LAIs relative to other treatment medications.
David Bin-Chia Wu_2013^Citation46	Hong Kong	Mirror-image study	2003–2007	191	Risperidone	Pre-post	3 years	HCRU; Cost;	Cost of hospitalization was significantly reduced after RLAI therapy. However, results should be considered as indicative or suggestive only, due to potential channeling bias where certain drug regimens are preferentially prescribed to patients with particular conditions. The findings from our study may be useful in health-care decision making considering treatment options for schizophrenia in resource-limited settings.
Fan Zhang_2015^Citation47	Multi center	Single arm trial	2010–2013	585	PP1M	Pre-post	1.5 years	PANSS; MSQ; AE;	PP was efficacious and generally tolerable with significant reductions observed in both number of hospitalizations and days spent in hospital.
Fuminari Misawa_2021^Citation48	Japan	Cohort study	2004–2019	5791	Aripiprazole; Risperidone; PP1M;	OAM-Risperidone/paliperidone	5 years	AE;	LAI-SGAs were not associated with a higher reporting frequency and mortality of NMS compared with oral SGAs, although clinicians need to closely monitor the occurrence of NMS not only during oral SGA treatment, but also, and in particular, in the early stage of LAI-SGA treatment.
Hongyan Zhang_2017^Citation49	Multi center	Single arm trial	2010–2013	728	PP1M	Pre-post	3.75 years	PSP	Functioning, including employment, was improved after short-term, once-monthly paliperidone palmitate injection, and was sustained to 18 months in Asia–Pacific patients with schizophrenia.
Hsiao-Fen Hsu_2019^Citation50	Taiwan region	Cohort study	2006–2015	78	FGA; SGA;	OAMs-Olanzapine, Risperidone, Ziprasidone, and Aripiprazole; LAI-FGA, SGA	3.5 year	HCRU;	We propose that oral and LAI antipsychotics were equally effective when patients received home care services. Our results can serve as a reference for the choice of treatment for patients with schizophrenia in a home care program.
Hsue-Wei Chan_2015^Citation51	Japan	Cohort study	2011–2012	379	Risperidone	OAMs- Risperidone	1 year	HCRU;	Using RLAI reduces the severity of disease in more difficult patients.
HuaFang Li_2016^Citation52	Multi center	Single arm trial	2012–2013	212	PP1M	Pre-post	1.5 years	PANSS; CGI-S; PSP; AE; discontinuation rate;	PP was generally tolerable and efficacious in a hospital setting for the treatment of acute exacerbated schizophrenia with significant improvements in psychotic symptoms, social functioning, and severity of illness.
Huafang Li_2018^Citation53	Multi center	Single arm trial	2012–2013	212	PP1M	Pre-post	13 weeks	PANSS; CGI-S; PSP; AE;	Early initiation of once-monthly paliperidone palmitate in hospitalized patients with acute exacerbation of schizophrenia led to greater improvements in psychotic symptoms with comparable safety than treatment initiation following 1 week of hospitalization.
Huaning Wang_2021^Citation54	Multi center	Cohort study	2012–2017	57,019	PP1M	OAM-SGAs	1 years	Adherence;	Persistence and adherence were significantly higher in PP1M users than in oral SGAs users across 3 databases comprising patients in 2 countries in Asia.
Hui-Chih Chang_2012^Citation55	Taiwan region	Mirror-image study	2004–2007	184	Risperidone	Pre-post	1 years	HCRU; Cost;	RLAI treatment was associated with reductions of service uses; however, overall psychiatric service costs were compromised by costs incurred from increased utilization of outpatient service and RLAI medication costs under the context of healthcare in the Taiwan region.
Jie Liu_2022^Citation56	Shandong Province	Mirror-image study	2016–2019	82	PP1M	Pre-post	2.5 years	HCRU; Cost;	Switching from OAPs to PP1M decreased the household workforce burden without increasing clinical healthcare costs. Direct costs were significantly reduced in patients with ≥ 1 inpatient stay in 1 year pre-PP1M treatment with OAPs after the switch, which decreased by improving adherence to therapy and reducing the number and length of hospital stays, suggesting that those patients may benefit after switching to PP1M.
Jingping Zhao_2017^Citation57	Multi center	Single arm trial	2013–2015	353	PP1M	Pre-post	4 weeks	PANSS; CGI-S; PSP; MSQ; AE; adherence; patients’ attitudes;	Long-term treatment with PP1M was efficacious, and no new safety concerns were identified in Chinese patients with schizophrenia. Overall, the results were comparable with observations from previous studies.
Jun Ishigooka_2015^Citation58	Multi center	RCT	NA	455	Aripiprazole	OAM-Aripiprazole	26 weeks	PANSS; CGI-S; relapse rate; AE;	Aripiprazole once-monthly is efficacious in maintenance treatment of stabilized schizophrenia, with comparable efficacy and tolerability to oral aripiprazole.
Jun Soo Kwon_2015^Citation59	Korea	Cohort study	NA	141	PP1M	NA	21 weeks	PANSS; PSP; MSQ; AE;	Switching from oral atypical antipsychotics to paliperidone palmitate because of poor satisfaction significantly improved patient satisfaction, with comparable efficacy and tolerability.
Junli Zhu_2021^Citation30	Beijing City	Cross-sectional study	2020–2020	496	LAIs	NA	2 months	Adherence; patients’ attitudes;	Beijing community patients are not very optimistic about LAI’s cognition and willingness. Medication habits play an important role in their medication selection decisions. Intervention such as educate clinicians and patients about LAI and provide free injections to patients can be imposed. The promotion of LAI still has a long way to go.
Le Xiao_2022^Citation60	Multi center	RCT	2017–2019	436	Aripiprazole	OAM-Aripiprazole	2 weeks	PANSS; CGI-S; PSP; AE;	This study confirmed the efficacy and safety of aripiprazole once-monthly (AOM) for the treatment of Chinese patients with acute schizophrenia. The non-inferiority of AOM to oral aripiprazole was established, with comparable efficacy and tolerability. These findings suggested that AOM could be used as a treatment option for patients experiencing an acute episode of schizophrenia.
Masakazu Hatano_2020^Citation61	Japan	Cohort study	2004–2018	5226	LAIs	OAMs- FGA, SGA. LAI: Risperidone, paliperidone; Aripiprazole	4.25 years	AE;	Real-world data suggest that LAIs tend to reduce the occurrence of extrapyramidal symptom and neuroleptic malignant syndrome, but a number of other adverse events have potential risks as well as OAPs. In addition, onset of adverse events with LAIs have been shown to be slightly delayed, requiring more careful long-term monitoring.
Mei Qiyi_2016^Citation62	Jiangsu Province	Single arm trial	2012–2013	156	PP1M	Pre-post	16 months	AE; discontinuation rate;	Gender, the third injection dose, PANSS reduction in acute phase and akathisia may be the main factors to discontinuation of PP treatment.
Miao Xingfang_2014^Citation63	Shandong Province	Single arm trial	NA	58	PP1M	Pre-post	13 weeks	PANSS; AE;	Paliperidone palmitate is an effective and safe long-acting injection antipsychotic. It shows good efficacy and safety profiles on first episode schizophrenia.
Nagahide Takahashi_2013^Citation64	Multi center	RCT	2010–2012	324	PP1M	Placebo	21 weeks	PANSS; CGI-S; AE;	PP is efficacious for Asian patients with schizophrenia at the dosing regimen approved in other countries, with a similar safety and tolerability profile.
Nam Young Lee_2014^Citation65	Korea	Single arm trial	2005–2007	472	Risperidone	Pre-post	1 year	PANSS; CGI-S; AE;	This prospective, open-label study showed improvements in symptom and AEs and a significant increase in BMI during 48 weeks of biweekly RLAI treatment. The rate of study completion was 39.0% and the remission rate among those who completed the study was 65.2%. None of the serious AEs were directly related to the administration of RLAI.
Nan Li_2018^Citation66	Multi center	Single arm trial	2012–2013	610	PP1M	Pre-post	1 years	PANSS; PSP;	Thus, symptom and functional improvements with caregiver burden reduction were observed in patients, and PANSS reduction at week 5 was commonly associated with favorable outcomes.
Nan Li_2019^Citation67	Multi center	Single arm trial	2010–2013	470	PP1M	Pre-post	12 months	Other	Switching to PP1M treatment from oral antipsychotics is likely to be associated with a significant reduction in hospitalization risk along with a delay in time to hospitalization and rehospitalization.
Po-Chung Ju_2014^Citation68	Taiwan region	Cohort study	1996–2009	1755	Risperidone;	OAMs	14 years	Other	Consequently, LAI home-based treatment for the prevention of schizophrenia relapse may lead to substantial clinical and economic benefits.
Qin Guoxing_2013^Citation69	Zhejiang Province	CCT	2007–2009	70	Risperidone	OAM-Risperidone	2.5 years	PANSS; relapse rate; AE;	Injection of long-active risperidone microsphere and risperidone tables have equivalent efficacy and safety, so it is a good choice for us to use the long- acting antipsychotic drug injection as a maintenance treatment of schizophrenia due to its inherent advantages of coerciveness.
Shiau-Shian Huang_2013^Citation70	Taiwan region	Cohort study	203–2008	14,610	LAIs; Risperidone; Haloperidol; Flupenthixol;	LAI-Risperidone, haloperidol, flupenthixol; OAM-risperidone, other SGA or FGA	5 years	Other	Except for injectable haloperidol, long-acting injectable antipsychotics seem not to be superior to oral antipsychotics in reducing rehospitalization.
Su-Chen Fang_2020^Citation71	Taiwan region	Cohort study	2011–2012	40,194	LAIs	OAM-FGA, Risperidone	1 year	HCRU;	Chronic schizophrenia patients who received only LAIs had a lower risk of disease relapse and a reduction in psychiatric service utilization than those receiving only OAPs.
Sung Woo Joo_2019^Citation72	Korea	Cohort study	2007–2016	6163	Haloperidol; PP1M; Risperidone;	PP1M-Haloperidol-Risperidone	10 years	Discontinuation rate;	Early discontinuation of LAI antipsychotic treatment occurs in a large number of patients with schizophrenia. Intervention strategies for improving the LAI antipsychotics treatment adherence are needed.
Sung-Wan Kim_2013^Citation73	Korea	Cross-sectional study	2011–2012	99	LAIs	NA	1 years	Patients’ attitudes;	In conclusion, attitudes of psychiatrists toward LAI were closely related to the use of LAI. The negative attitudes and reluctance of psychiatrists, rather than patient resistance, may contribute toward the underuse of LAI.
Szu-Jui Fan_2018^Citation74	Taiwan region	Cohort study	2008–2013	2073	Risperidone	OAM- Risperidone	1 year	HCRU; Cost;	Patients with schizophrenia treated with RLAI had shorter lengths of stay, higher medical costs largely because of increased utilization of outpatient service and hospital admissions, compared with those who took risperidone orally.
Tang Wei_2016^Citation75	Zhejiang Province	RCT	2012–2014	120	PP1M	OAM-Risperidone	2.5 years	PANSS; PSP; relapse rate; AE;	Long-acting paliperidone palmitate injection in the treatment of the patients with schizophrenia could obviously improve the remission rate.
Tianmei Si_2015^Citation76	Multi center	Single arm trial	2012–2013	610	PP1M	Pre-post	1 years	PANSS; CGI-S; PSP; MSQ; AE; adherence; patients’ attitudes;	The efficacy and safety data are consistent with other short-term, placebo-controlled studies of paliperidone palmitate conducted in similar populations.
Tianmei Si_2018^Citation77	Multi center	Single arm trial	2012–2014	362	PP1M	Pre-post	1 year	Relapse rate; AE; adherence;	Continued use of PP1M formulation/LAI antipsychotic was effective in preventing schizophrenia relapses, especially in patients with suboptimal antipsychotic adherence.
Tianmei Si_2019^Citation78	Multi center	Single arm trial	2010–2013	108	PP1M	Pre-post	3 years	PANSS; PSP; MSQ; AE;	Efficacy of PP1M corroborate findings from earlier studies and no new safety concerns emerged in this Chinese subgroup of patients with schizophrenia.
Wang Jian_2015^Citation79	Hebei Province	RCT	2013–2013	60	PP1M	OAM-Risperidone	13 weeks	PANSS; CGI-S; PSP;	Palmitic acid Paley piperidone is effective in the treatment of schizophrenia, which is beneficial to the patient’s continuous and effective drug treatment and the improvement of the social life function of the patients.
Wen-Yin Chen_2016^Citation80	Taiwan region	Cross-sectional study	2013–2014	434	FGA; Risperidone;	LAI-FGA	1 years	CGI-S; PSP;	Our results suggest that patients treated with FGA-LAI have more satisfactory subjective experiences compared with patients treated with RIS-LAI and that both FGA-LAI and RIS-LAI treatments can prevent relapses and hospitalization. Additional longitudinal studies determining the long-term benefits of RIS-LAI are warranted.
Xu Qiuxia_2015^Citation81	Zhejiang Province	RCT	2012–2013	72	PP1M	OAM-Risperidone	14 months	PANSS; PSP; AE;	Palmitic acid Paley piperidone is effective and rapid in the treatment of acute schizophrenia, with significant social functioning improvement, convenience, and satisfaction.
Yosuke Koshikawa_2016^Citation82	Japan	RCT	2014–2015	30	PP1M; Risperidone;	PP1M; Risperidone;	0.5 years	Other	These results suggest that PP may improve the total social functioning, independent life competence, and performance as compared to the RLAI group. However, these results are preliminary and need independent replication in larger samples before any definitive statement can be made.

Abbreviations: AE, adverse event; AOM, aripiprazole once-monthly; CCT, controlled clinical trial; CGI-S, the Clinical Global Impression - Severity of Illness Scale; FGA, first-generation antipsychotics; HCRU, healthcare resource utilization; LAI, long-acting injectable; MSQ, the Medication Satisfaction Questionnaire; NA, not applicable; OAM, oral antipsychotic medications; OAP, oral antipsychotics; PANSS, the Positive and Negative Syndrome Scale; PP, palmitate paliperidone; PP1M, palmitate paliperidone once-monthly; PP3M, palmitate paliperidone 3-monthly; PSP, the Personal and Social Performance Scale; RCT, randomized controlled trial; RLAI, risperidone long-acting injectable; SGA, second-generation antipsychotics.

Figure 1 Flowchart of the study selection process.

Abbreviations: LAI, long-acting injectable; CNKI, Chinese National Knowledge Infrastructure.

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