Clinical,Quality of Life,and Health Care Utilization Outcomes of Switching the Administration Route of Antipsychotic Medications Among People With Schizophrenia Spectrum Disorder: A Systematic Review and Meta-Analysis

Abstract

Background:

Using long-acting injectable (LAI) antipsychotic medications can improve the outcomes of patients with schizophrenia, such as reducing symptom severity and hospitalization risk. However, the outcomes of switching from oral to LAI antipsychotic medications are unclear.

Aims:

The purpose of this review is to provide a summary of the clinical, quality of life, and health care utilization outcomes of switching from oral to LAI antipsychotics among patients with Schizophrenia Spectrum Disorder.

Methods:

We thoroughly searched the PubMed, Scopus, PsycInfo, and CINAHL databases. To conduct the meta-analysis, we used the Comprehensive Meta-Analysis Program.

Results:

Forty-one articles met our inclusion criteria. After switching to LAIs, symptom severity, the number of rehospitalizations, emergency department visits, and overall health care costs were reduced. Also, social functioning significantly improved. However, no differences were observed in the frequency of outpatient visits. Pharmacy costs were increased between pre- and post-LAI initiation.

Conclusion:

Our findings support evidence that changing the route of administration of antipsychotic medications from oral to long-acting intramuscular injections can improve the clinical, quality of life, and health care utilization outcomes in people with schizophrenia. Health care practitioners might consider encouraging LAI use earlier during treatment for schizophrenia for better clinical outcomes and to reduce health care utilization associated with treatment.

Keywords

schizophrenia symptoms severity rehospitalization outpatient and emergency visits

The primary goal of using antipsychotic medications to treat those living with schizophrenia spectrum disorder is to decrease symptom severity, prevent relapse, and improve overall clinical outcomes (Keepers et al., 2020). A persistent challenge in treating people with schizophrenia is to maintain the continuity of effective, well-tolerated antipsychotic therapy that provides adequate symptom control and clinical stability (Haddad et al., 2014). In fact, non-adherence to antipsychotic medications varies widely, ranging from 11.0% to 71.9% (Ljungdalh, 2017; Yaegashi et al., 2020). Moreover, relapse after the first episode of psychosis ranges from 19.4% to 97.0% among people with schizophrenia (Bowtell et al., 2018). Given these varying rates of non-adherence and relapse, finding ways to support medication management is essential.

Medication management for symptoms of schizophrenia currently involves two main formulations of antipsychotic medications: oral and long-acting injectables (LAIs). After initiating an oral antipsychotic medication, it is not uncommon for people to switch to another. Studies have explained that patients switch between antipsychotic medications because of inconsistent adherence and poor tolerance of side effects (Huang et al., 2021; Keks et al., 2019; Newcomer et al., 2013). LAIs are considered an important means of supporting adherence and preventing symptom relapse with similar tolerability and efficacy profiles between first-generation and second-generation formulations (Biagi et al., 2017; Rubio et al., 2020; Uribe et al., 2020; Zolezzi et al., 2021). When considering initiating an LAI, expert consensus panels emphasize consideration of oral efficacy and tolerability as well as the potential use of LAIs earlier in the course of schizophrenia (Sajatovic et al., 2018a, 2018b). Moreover, providers, who practice from a patient-centered, recovery-oriented approach, view LAI initiation as crucial in further preventing functional declines, desocialization, reduced mortality, and promoting adherence to medications (Fang et al., 2022; Pietrini et al., 2019). Hence, it is important to examine both clinical and recovery-centered outcomes of LAI initiation for people with schizophrenia. Recent studies have reported possible advantages of using LAIs early in the course of schizophrenia treatment. In particular, they suggested that early LAI initiation within the first year of schizophrenia episodes may benefit treatment management, adherence, relapse rates, and other outcomes, resulting in lower hospitalization rates and health care expenditures (Kane et al., 2023; Munday et al., 2019).

Previous reviews have also investigated the impact of switching from oral to LAIs among schizophrenia patients. These reviews examined the effect of LAIs on medication adherence, hospitalization risks, relapse, emergency department (ED) visits/admission, or health care costs compared to oral antipsychotic medications (Kishimoto et al., 2013, 2021; Lin et al., 2021). In general, these studies determined that LAIs are often superior to oral drugs in terms of medication adherence, hospitalizations, and ED visits, but not health care costs. However, no known published studies have conducted a comprehensive review and meta-analysis on the effect of switching the administration route of antipsychotic medications from oral to intramuscular injections on both clinical and recovery-focused (e.g., quality of life) outcomes. Our current review includes recent research updates and includes additional outcomes of importance, including symptom severity and social functioning, which have not been included in prior meta-analyses.

Therefore, the purpose of this review was to synthesize the known studies that have examined the effect of switching the administration route of antipsychotic medications from oral to intramuscular injections in people with schizophrenia spectrum disorder. Specifically, we (a) conducted a systematic review on the effectiveness of switching from orals to LAIs on clinical outcomes (i.e., symptom severity, rehospitalization, outpatient, and ED visits), quality of life (i.e., social functioning), and health care utilization (i.e., health care costs) as primary outcomes and (b) performed a meta-analysis on the effectiveness of changing antipsychotic administration route on clinical, quality of life, and health care utilization.

Methods

The preregistered protocol for this systematic review was submitted to PROSPERO (registration number CRD42021249844). Our process was guided by the Preferred Reporting Item for Systematic Reviews and Meta-Analyses (PRISMA) (Page et al., 2021). We searched for indexed studies in the PsycInfo, CINAHL, Scopus, and PubMed databases. The following sets of keywords were used: “Fluphenazine Decanoate AND Haloperidol Decanoate AND Aripiprazole Monohydrate AND Aripiprazole Lauroxil AND Olanzapine Pamoate AND Paliperidone Palmitate AND Risperidone Microspheres,” “Adherence AND Outpatient Visit AND Hospitalization AND Incarceration AND Readmission,” and “Schizophrenia OR Schizoaffective OR Psychotic disorder.” All articles that matched our inclusion criteria were included in our search.

Inclusion and Exclusion Criteria

We included English-language studies published before August 2020 from peer-reviewed journals that compared outcomes before and after changing antipsychotic administration route from an oral to an LAI. We excluded meta-analyses, review articles, and non-quantitative studies.

Study Selection

Two authors (Authors 1 and 2) conducted the searches and initial screening of articles. The EndNote program was used to pool the retrieved articles, and all duplicates were removed. To select relevant articles, titles were initially screened, then, abstracts were assessed, and finally, the full texts of the retrieved articles were examined. The screeners produced a final list of relevant articles, and any disagreements over an article’s eligibility were resolved through discussion with another reviewer (Author 4).

Appraisal of Methodological Quality

Independent reviewers screened all included articles (Authors 1, 2, and 3). Two different quantitative checklists were used for critical appraisal that assess similar aspects of studies (Kmet et al., 2004; Ma et al., 2020). The first checklist was rated on a three-point scale (0 = No, 1 = Partial, and 2 = Yes). The total score for all 14 items was added and then divided by 28 (the highest number to be given) to calculate the summary score for each paper (Kmet et al., 2004). The second checklist was by the National Institutes of Health (NIH), which assessed the quality of pre-post studies (Ma et al., 2020). It includes 12 items rated as 0 = No or 1 = Yes. Results of the critical appraisal were presented in both quantitative and narrative forms. SPSS Version 28 was used to assess the inter-rater reliability among raters.

Data Extraction

Two reviewers independently (Authors 1 and 2) extracted the data. The data extraction forms included author and publication year, country where the study was conducted, design, participant characteristics, main outcomes, time points of study outcomes, and main findings.

Main Outcome Measures

Symptom severity was assessed using the Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), and Clinical Global Impression (CGI) scales. The PANSS includes 30 items rated from 1 (absent) to 7 (extreme). It is divided into three subscales: positive symptoms, negative symptoms, and general psychopathology. The PANSS has good inter-rater reliability and adequate construct validity (Kay et al., 1987, 1988). The second scale was the GAF, which measures mental health by rating the patient’s psychological, social, and occupational functioning on a scale of 0 to 100. The validity of assigned GAF ratings often correlates more strongly with the intensity of symptoms than with degree of impairment, especially when the severity and degree of functional impairment are incongruent (Endicott et al., 2008; Schwartz, 2007). Also, the CGI was used to measure symptom severity and treatment efficacy and has good reliability and moderate validity. The CGI is rated on a seven-point scale and includes three subscales: illness severity, global improvement, and therapeutic response (Allen et al., 2012; Ventura et al., 2008).

The Personal and Social Performance (PSP) Scale was used to assess social functioning. The PSP is a six-point Likert-type scale that includes four domains: social activities, personal and social relationships, self-care, and disturbing and aggressive behaviors. Different studies have supported the validity and reliability of the PSP scale (Nafees et al., 2012; Nasrallah et al., 2008).

To assess hospitalizations and outpatient and ED visits, we used the mean number of visits. The examining studies assessed outpatient and ED visits by collecting data from the year before (pre-LAI period) and the year after the index date (the start of the LAI period) and determining the mean number of visits. Health care and pharmacy costs were determined at the patient level as an average monthly cost before and after LAI.

We pooled the effect from studies that used the same statistical approaches and measurements. The Comprehensive Meta-Analysis (CMA) software Version 3 was used to analyze the data (Borenstein et al., 2013). Random-effects modeling was used to determine overall effect sizes as well as standardized mean differences (SMDs) and associated 95% confidence intervals (CIs). An SMD less than zero with p < .05 indicates a significant difference between treatment conditions. The heterogeneity of true effects was tested using prediction intervals for outcomes involving at least 10 studies, and $τ^{2},$ I², Q, and p-values were provided. Egger’s regression test (Egger et al., 1997) and Duval and Tweedie’s trim and fill approach (Duval & Tweedie, 2000) were used to examine publication bias for outcomes with at least 10 studies.

We used the Joanna Briggs Institute (JBI) System for the Unified Management, Evaluation, and Review of Information to conduct a narrative synthesis (Moola et al., 2017). The key findings from each study were then classified based on our primary outcomes of interest (symptom remission, rehospitalizations, outpatient and ED visits, health care costs, and social functioning).

Results

Studies Description

Initially, 1,587 articles were found in the research (see PRISMA flow chart, Supplementary Figure S1). Excluding duplicates, 41 studies met all inclusion criteria. Based on the two raters, the mean score of the included studies (using the NIH tool) was 8.720 (intraclass correlation coefficient r = .464, p = .023), and the average score for the included studies using the Kmet tool was 18.488 (intraclass correlation coefficient r = .808, p = .001). The quality of all included studies (N = 41) was graded as fair, with a bias risk due to the absence of blinding and not using the interrupted time series design to measure the outcomes of interest.

The total number of patients with schizophrenia who switched from oral to LAIs in the included studies was 15,754. The mean sample size of all included studies was 384.24 (range = 21–3,094). The following narrative and meta-analysis results are categorized according to the primary outcomes of interest.

Narrative Analysis

Symptom Remission

Ten studies measured PANSS scores from before to after LAI treatment. From the baseline of each study to its endpoint, the PANSS total score significantly declined (Table 1). Also, 10 studies reported significant reductions in the CGI scores after switching to LAIs (see Table 1). Finally, five studies reported that the GAF scores were significantly improved from baseline to endpoint (Table 1).

Table 1.

Characteristics of Included Studies.

Author (year) and country	Study design	Sample description	Measures	Time points of study	Key findings
Positive and Negative Syndrome Scale (PANSS)
1. Kwon et al., 2015, Korea	Prospective RCT	N = 134 Age = 34.3 years Male = 50.4% Oral Antipsychotics vs. Long-Acting Injectable (LAI) Immediate switch group = 67 Delayed switch group = 67	PANSS	21 weeks	There were significant decreases in the total PANSS scores from baseline to final visit for both the immediate switch group (from 72.8 ± 23.4 to 67.4 ± 22.4, p = .0135) and the delayed switch group (from 74.4 ± 20.4 to 69.6 ± 20.8, p = .005).
2. Emsley et al., 2017, Croatia, Italy, Russia, and Turkey	Retrospective study	N = 84 Age = 24.1 years Male = 69.0% Oral antipsychotic (n = 72) vs. Paliperidone Palmitate Once-Monthly (PP1M; n = 72)	PANSS	12 months	There was a significant decrease in mean PANSS scores from baseline (95.8) to endpoint (64.2) (mean change = 31.6 ± 21.1, p < .001).
3. Marinis et al., 2007, 22 European countries	Secondary analysis	N = 565 Age = 41.3 years Male = 66.4% Oral Conventional Antipsychotic vs. Risperidone Long-Acting Injectable (RLAI)	PANSS	6 months	There was a significant decrease in the total PANSS scores which changed by 15.3 ± 17.5 (p = .0001) points for patients who switched from oral conventional to RLAI.
4. Li et al., 2019, Asian patients from China, Hong Kong, Korea, Malaysia, Philippines, Taiwan, and Thailand	Prospective study	N = 121 Age = 36.2 years Male = 59.5% Tolerability to oral paliperidone or oral risperidone was performed ≤ 1 week before initiating PP1M, n = 121 Tolerability to oral paliperidone or oral risperidone was performed > 1 week before initiating PP1M, n = 91 Oral antipsychotics vs. PP1M	PANSS	13 months	The mean total PANSS score significantly reduced from baseline to endpoint (from 89.1 ± 14.99 to −26.4 ± 19.38, p ≤ .0001).
5. Enătescu et al., 2020, Romania	Pre- and post-study	N = 21 Age = 38.5 years Male = 57% Oral Antipsychotics vs. Depot Long-Acting Antipsychotics (LAIs)	PANSS	12 months	There was a significant decrease in PANSS scores after switching to LAI between baseline, 6 months, and 12 months, p < .001.
6. Devrimci-Ozguven et al., 2019, Finland	Retrospective study	N = 222 Age = 65 years Male = 68.3% Oral Paliperidone Palmitate (PP) vs. PP injection	PANSS	12 months	Compared to the period before PP injections, the median of PANSS during PP injections treatment significantly decreased (from 91 [range = 47–196], 95% CI = [88.6, 100.4] to 59 [range = 30–136], 95% CI = [60.5, 70.0], p < .001).
7. Zhang et al., 2015, Asia Pacific region, Republic of China, Hong Kong, Korea, Malaysia, New Zealand, Philippines, Taiwan, and Thailand.	Pre-post study	N = 521 Age = 28.7 Male = 65.5% Oral Antipsychotics vs. LAI PP	PANSS	18 months	PANSS score decreased significantly from baseline to month 18 (from 64.1 ± 19.1 to 52.7 ± 2.3) and the mean change was −11.3 ± 21.4, p < .001.
8. Schmauss et al., 2007, International trial; Europe	Secondary data analysis (Moller et al., 2005)	N = 572 Age = 38.3 years Male = 60.0% Oral Risperidone vs. Risperidone Long-Acting Injectable	PANSS	6 months	PANSS mean scores decreased from baseline to study endpoint (from 71.9 ± 22.4 to 61.7 ±22.6, p ≤ .0001).
9. Si et al., 2016, China	Prospective study	N = 610 Age = 31.3 years Male = 60.5% Oral antipsychotic (risperidone/paliperidone ER, n = 263; olanzapine, n = 52; other antipsychotics, n = 293) vs. PP1M	PANSS	13 weeks	After switching to PP1M, the PANSS total mean score reduced from baseline to the endpoint for risperidone/paliperidone ER (from 91.8 ± 12.4 to −31 ± 18.4, p < .001), for olanzapine (from 87.7 ± 12.5 to −25.5 ± 20, p < .001), and for other antipsychotics (from 92.4 ± 12.5 to −31.7 ± 20.4, p < .001).
10. Rosa et al., 2012, France, Kuwait, Portugal, and Saudi Arabia	Prospective study	N = 96 Age = 40.2 years Male = 77.1% From Atypical Antipsychotic, Oral Olanzapine to RLAI	PANSS	26 weeks	From baseline to endpoint, there were decreases in PANSS total scores (from 84.1 ± 23.1 to 64.5 ±22.6, mean change = −19.6, 95% CI = [−23.9, −15.3], p < .0001).
Clinical Global Impression (CGI)
1. Emsley et al., 2017, Croatia, Italy, Russia, and Turkey	Retrospective study	N = 84 Age = 24.1 years Male = 69.0% Oral antipsychotic (n = 68) vs. PP1M (n = 68)	CGI	12 months	There was a statistically significant decrease in mean CGI from baseline (5.0) to endpoint (2.5), the mean change was −2.5 ± 1.1; p = .001.
2. Li et al., 2019, Asian patients from China, Hong Kong, Korea, Malaysia, Philippines, Taiwan, and Thailand	Prospective study	N = 121 Age = 36.2 years Male = 59.5% Tolerability to oral paliperidone or oral risperidone was performed ≤ 1 week before initiating PP1M, n = 121 Oral antipsychotics vs. PP1M	Clinical Global Impression-Severity (CGI-S)	13 months	The mean total CGI-S significantly decreased from baseline to week 13 (from 4.9 ± 0.78 to −1.5 ± 1.21, p ≤ .0001).
3. Girardi et al., 2010, Italy	Pre- and post-study	N = 88 Age = 41.2 years Male = 64.8% Oral Antipsychotic vs. RLAI	Clinical Global Impression-Schizophrenia Scale (CGI-SCH)	6 months	Compared to the oral antipsychotic period, in the RLAI period patients showed decreases in CGI-S scores (mean change = −83.0 ± 5.47, p < .001).
4. Fefeu et al., 2018, The United States	Retrospective study	N = 136 Age = 42.6 years Male = 67.5% Oral Olanzapine vs. Olanzapine Long-Acting Injections (OLAIs)	CGI-SCH	12 months	There was 63.2% reduction in the overall severity score of the CGI-SCH after the initiation of the OLAIs (from 5.50 ± 1.19 to 2.02 ± 0.83, p < .0001).
5. Di Lorenzo et al., 2018, Italian	Pre- and post-study	N = 50 Age = 43.1 years Male = 52.0% Pre- and post-PP1M	Clinical and Global Impression-Improvement Scale (CGI-I)	12 months	There were improvements in CGI-I (t = 1.29, p = .02).
6. Devrimci-Ozguven et al., 2019, Finland	Retrospective study	N = 222 Age = 65.0 years Male = 68.3% Oral PP vs. PP1M	Clinical and Global Impression-Severity scale (CGI-S)	12 months	Compared to the period before PP injections, the median of CGI-S scores during PP injections treatment significantly reduced (5 [3–7] vs. 4 [1–6], p < .001).
7. Marinis et al., 2007, 22 European countries	Secondary analysis	N = 565 Age = 41.3 years Male = 66.4% Oral Conventional Antipsychotic vs. RLAI	CGI-S	6 months	Patients switching from oral to RLAI showed decreases in CGI-S (from 3.7 ± 1.2 to 3.2 ± 1.3, p < .01).
8. Zhang et al., 2015, Asia Pacific region, Republic of China, Hong Kong, Korea, Malaysia, New Zealand, Philippines, Taiwan, and Thailand.	Pre-post study	N = 521 Age = 28.7 years Male = 65.5% Oral Antipsychotics vs. LAI PP	Clinical Global Impression of Schizophrenia (CGI-SCH)	18 months	CGI-SCH score reduced significantly from baseline to the 18 months (from 3.4 ± 1.10 to −0.8 ± 1.35, p < .001).
9. Si et al., 2016, China	Prospective study	N = 610 Age = 31.3 years Male = 60.5% Oral antipsychotic (risperidone/paliperidone ER, n = 263; olanzapine, n = 52; other antipsychotics, n = 293) vs. PP1M	CGI-S	13 weeks	After switching to PP1M, Patients showed significant reductions (p < .001) from baseline to the endpoint on the CGI-S score for risperidone/paliperidone ER (from 5.2 ± 0.7 to −1.8 ± 1.3) for olanzapine (from 5.3 ± 0.7 to −1.7 ± 1.3) and for other antipsychotics (from 5.3 ± 0.7 to −1.9 ± 1.3).
10. Rosa et al., 2012, France, Kuwait, Portugal and Saudi Arabia	Prospective study	N = 96 Age = 40.2 years Male = 77.1% From Atypical Antipsychotic, Oral Olanzapine to RLAI	CGI-S	26 weeks	From baseline to endpoint, there were significant reductions in CGI-S scores (from 3.8, SD = 1 to. 3.1, SD = 1.2, p < .0001).
Global assessment functioning
1. Emsley et al., 2017, Croatia, Italy, Russia, and Turkey	Retrospective study	N = 84 Age = 24.1 years Male = 69.0% Oral antipsychotic (n = 47) vs. PP1M (n = 47)	Global Assessment of Functioning (GAF)	12 months	There was a statistically significant increase in mean GAF scores from baseline (38.7) to endpoint (64.9); the mean change was 26.1 ± 12.3; p = .001.
2. Marinis et al., 2007, 22 European countries	Secondary analysis	N = 565 Age = 41.3 years Male = 66.4% Oral Conventional Antipsychotic vs. RLAI	GAF	6 months	From baseline to endpoint, there was significant increase in GAF scores (from 57.6 ± 15.9 to 63.2 ±17.2, p ≤ .001).
3. Di Lorenzo et al., 2018, Italian	Pre- and post-study	N = 50 Age = 43.1 years Male = 52.0% Pre- and post-PP1M	GAF	12 months	There were improvements in GAF scores (t = 4.55, p = .000).
4. Devrimci-Ozguven et al., 2019, Finland	Retrospective study	N = 222 Age = 65.0 years Male = 68.3% Oral PP vs. PP injection	GAF	12 months	The median GAF significantly improved during PP injections treatment compared to oral treatment (from 41, 95% CI = [10, 75] to 61, 95% CI = [30, 95], p < .001).
5. Rosa et al., 2012, France, Kuwait, Portugal and Saudi Arabia	Prospective study	N = 96 Age = 40.2 years Male = 77.1% From Atypical Antipsychotic, Oral Olanzapine to RLAI	GAF	26 weeks	From baseline to endpoint, there were significant increases in GAF scores (from 55 ± 16.8 to 64.2 ± 17.4, p < .0001).
Rehospitalizations
1. Kane et al., 2013, North America	Pre-post study	N = 183 Age = 42.2 years Male = 69.4% Oral Antipsychotic (n = 104) vs. Aripiprazole Once Monthly (n = 79)	Total Psychiatric hospitalization rates (Proportion of patients with ≥1 psychiatric hospitalization)	6 months	Hospitalization rates were significantly lower in the post-period compared with the pre-period (from 14.2% to 41.5%, rate ratio = 0.34; p < .0001).
2. Kane et al., 2015, North America	Naturalistic study with prospective/Retrospective design	N = 433 Age = 42.7 years Male = 69.5% Oral Antipsychotic Therapy vs. Aripiprazole Once Monthly 400 mg (AOM 400)	Total Psychiatric hospitalization rates (Proportion of patients with ≥1 psychiatric inpatient hospitalization)	6 months	Psychiatric hospitalization rates were significantly lower after patients switched from oral to AOM 400 (from 38.1% to 8.8%, p < .0001).
3. Hsia et al., 2017, the United States	Pre-post study	N = 75 Age = 48.5 years Male = 90.7% Oral Risperidone vs. Paliperidone LAI	Hospitalization days	6 months	Switching from oral risperidone to paliperidone LAI was associated with significant decreases in the median hospitalization days (from 15.0 to 0.0, p < .001).
4. Marinis et al., 2007, 22 European countries	Secondary analysis	N = 565 Age = 41.3 years Male = 66.4% Oral Conventional Antipsychotic vs. RLAI	Proportion of patients hospitalized	6 months	Proportion of patients hospitalized decreased for patients who switched from conventional oral to RLAI (from 17.2% to 12.0%, p = na).
5. Leal et al., 2004, Austria, Canada, the Czech Republic, Denmark, France, Germany, the Netherlands, Norway, Poland, Sweden, Switzerland, and the United Kingdom	Prospective study	N = 397 Age = 43.6 years Male = 63.0% Oral Risperidone vs. RLAI	Proportion of patients requiring hospitalization	12 months	The proportion of patients requiring hospitalization decreased after Long-Acting Risperidone (from 38.0% to 12.0%, p < .0001).
6. Koczerginski & Arshoff, 2011, Canada	Retrospective study	N = 25 Age = NA Male = NA Oral therapy vs. RLAI	Annual average admissions per patient Average annual hospital days per patient	12 months	Compared to the oral treatment period, the annual average admissions per patient were lower during the RLAI period (1.7 vs. 0.2, p = na) and average annual hospital days per patient was shorter (34.7 days vs. 2.6 days, p = na). In the RLAI treatment period, the hospitalization rate was 8.5 (95% CI = [3.5, 20.4]) times lower than during the oral treatment period, p < .0001.
7. Fefeu et al., 2018, the United States	Retrospective study	N = 136 Age = 42.6 years Male = 67.5% Oral Olanzapine vs. OLAIs	Mean number of psychiatric hospital admissions Number of hospital bed days	12 months	The mean numbers of psychiatric hospitalization admissions were reduced by 65.8% after the initiation of the OLAIs (from 2.10 ± 1.76 to 0.72 ± 1.35, p < .0001). The mean numbers of hospital bed days were reduced by 86.2% after the initiation of the OLAIs (from 58.00 ± 52.45 to 7.97 ± 15.78 days, p < .0001).
8. Enătescu et al., 2020, Romania	Pre- and post-study	N = 21 Age = 38.5 years Male = 57.1% Oral Antipsychotics vs. Depot Long-Acting Antipsychotics (LAIs)	Number of psychiatric hospitalizations	12 months	There was a statistically significant decrease in the number of hospitalizations after starting LAI (p = .003).
9. Di Lorenzo et al., 2018, Italian	Pre- and post-study	N = 50 Age = 43.1 years Male = 52.0% Pre- and post-PP1M	Numbers of psychiatric hospitalizations	12 months	PP1M treatment significantly reduced the number of psychiatric hospitalizations (t = 2.3, p < .05).
10. Devrimci-Ozguven et al., 2019, Finland	Retrospective study	N = 222 Age = 65.0 years Male = 68.3% Oral PP vs. PP injection	Median number of hospitalizations	12 months	Compared to the period before PP injections, the median number of hospitalizations during PP injections treatment was significantly decreased (2 [0–10] vs. 0 [0–4], p < .001).
11. Patel, Emond, et al., 2020, the United States	Retrospective study	N = 427 Age = 41.1 years Male = 62.1% Oral Risperidone or Oral Paliperidone vs. PP1M	Number of inpatient stays per month Number of days spent in an inpatient setting per month	6 months	Number of inpatient stays decreased after switching to PP1M (from 0.13 ± 0.21 to 0.06 ± 0.17, p < .001) and days spent in an inpatient setting decreased per month (from 1.30 ± 3.47 to 0.61 ± 1.75, p < .001).
12. Zhang et al., 2015, Asia Pacific region, Republic of China, Hong Kong, Korea, Malaysia, New Zealand, Philippines, Taiwan, and Thailand.	Pre-post study	N = 521 Age = 28.7 years Male = 65.5% Oral Antipsychotics (n = 471) vs. LAI PP (n = 407)	Mean number of hospitalization days/person/year Percentage of patients requiring hospitalization	12 months	PP significantly reduced the mean number of hospitalization days/person/year (from 74.25 to 19.77, p < .0001). PP significantly decreased the percentage of patients requiring hospitalization in past 18 months (from 39.7% to 24.6%, p < .001).
13. Oh et al., 2019, South Korea	Retrospective study	N = 46 Age = 46.3 years Male = 45.7% Oral Antipsychotics vs. Long-Acting Injectable Antipsychotics Paliperidone Palmitate (LAI-PP)	Average number of admissions Mean total number of bed days	12 months	Average number of admissions decreased significantly before and after PP (from 0.83 ± 0.95 to 0.17 ± 0.38, p < .0002). The mean total number of bed days decreased significantly from before and after PP (from 24.85 ± 33.77 to 8.74 ± 14.98, p < .006).
14. Willis et al., 2010, Sweden	Retrospective study	N = 77 Age = 44.6 years Male = 57.0% Atypical Oral Antipsychotic vs. Risperdal Consta	Hospital bed days/year/patient Hospitalization/ year/patient	12 months	There was a 45% significant reduction in hospitalization bed days/year/patient (from 38.94 ± 3.83 to 21.5 ± 3.36, p = .000). There was a 27% significant reduction in hospitalization/year/patient (from 0.86 ± 0.07 to 0.63 ± 0.09, p = .011).
15. Tegeler & Lehmann, 1981, Germany	Pre-post study	N = 78 Age = 44.3 years Male = NA Short-Acting medication vs. Long-Acting medication	Mean number of readmissions Average duration of hospital stays	5 years	The number of readmissions was decreased during the long-acting medication treatment period compared to the short-acting medication treatment period (from 0.80 to 0.20, p < .001). The average duration of hospital stay was decreased during the long-acting medication treatment period compared to the short-acting medication treatment period (from 35 to 6 weeks, p < .001).
16. Schmauss et al., 2007, International Trail; Europe	Secondary data analysis (Moller et al., 2005)	N = 572 Age = 38.3 years Male = 60.0% Oral Risperidone vs. Risperidone LAI	Number of hospitalization status	6 months	From baseline to endpoint, the number of hospitalizations was reduced (from 247 to 78, p = na).
17. Olivares et al., 2008, Spain	Retrospective and prospective study	N = 788 Age = 39.3 years Male = 61.5% Pre- vs. Post-LAI Risperidone	Total number of patients requiring psychiatric inpatient care	Pre 12 months, post 24 months	There were a higher number of patients not requiring hospitalization after switching to LAI risperidone (from 645 to 454, p = na).
18. Niaz & Haddad, 2007,	Retrospective study	N = 74 Age = 39.9 years Male = 60.8% From Oral Antipsychotic to RLAI	Number of admissions Total number of days of psychiatric inpatient care	35 months	In post-RLAI, there was a reduction in the number of admissions (from 65 to 33, p < .005) and in total inpatient days (from 4,550 to 2,188 days, p < .005).
19. Chang et al., 2012, Taiwan	Pre- and post-study	N = 184 16–35 years old = 31.0% 36–55 years old = 60.3% 56 years and over = 8.7% Male = 50.5% From Oral Antipsychotics to RLAI	Total annual number of admissions and numbers of hospital days	12 months	Compared to the pre-RLAI period, the total annual number of acute admissions were reduced by 57% (from 142 to 61, p < .0001), and total hospital days were reduced by 49% (from 6,499 to 3,312, p < .0001) in the post-RLAI period.
20. Rosa et al., 2012, France, Kuwait, Portugal and Saudi Arabia	Prospective study	N = 96 Age = 40.2 years Male = 77.1% From Atypical Antipsychotic, Oral Olanzapine to RLAI	Mean number of hospitalization days	26 weeks	Mean number of hospitalizations days for the total sample were 4.9 ± 17.6 days from baseline to week 12, and 1.4 ± 8.2 days during weeks 12–26, p = na.
21. Crivera et al., 2011, the United States	Prospective study	N = 435 Age = 41.9 years Male = 66.7% Pre- vs. post-Risperidone Long-Acting Therapy (RLAT)	Number of hospitalizations (all-cause and psychiatric-related) Number of hospitalizations (psychiatric-related)	12 months	After initiation with RLAT, the mean number of hospitalizations for any reason was decreased (from 0.71 to 0.42, p < .01). After initiation with RLAT, the mean number of psychiatric-related hospitalizations decreased (from 0.63 to 0.28, p < .01).
22. Ren et al., 2011, the United States	Pre- and post- study	N = 924 Age = 51.4 years Male = 93.6% Pre- vs. Post-RLAT	Number of psychiatric hospitalizations Number of psychiatric hospitalization days	12 months	The number of psychiatric hospitalizations/patients decreased by 0.35 (from 1.36 ± 1.49 to 1.01± 1.63; p < .0001). The mean number of psychiatric hospitalization days/patient decreased by 6.5 days (from 20.0 ± 36.0 to 13.6 ± 35.8; p < .0001).
23. Peng et al., 2011, the United States	Pre- and post-study	N = 147 Age = 42.6 years Male = 53.7% Pre- vs. Post-Risperidone Long-Acting Therapy (RLAT)	Hospitalization rates Inpatients psychiatric admission Days hospitalized for any reason. Days hospitalized for psychiatric reasons	6 months	Psychiatric hospitalizations decreased (from 79 pre-initiation to 44 post-initiation, p < .001). The mean of inpatient psychiatric admissions decreased (from 0.67 ± 0.80 to 0.31 ± 0.65, p < .001). The mean of the days hospitalized for any reason decreased (from 9.0 ± 12.2 to 5.3 ± 13.2, p = .067). The mean of the days hospitalized for psychiatric reasons decreased from 7.27 ± 11.6 to 4.73 ± 13.1, p = .054.
24. Su et al., 2009, Taiwan	Pre- and post-study	N = 108 Age = 42.0 years Oral Risperidone, FGAs, or SGAs vs. RLAI	Numbers of acute admissions Hospital days	12 months	Compared to the oral group, there were significant reductions in the total annual numbers of acute hospital admissions by 55% (from 80 to 36, p = .0003) and hospital days by 48% (from 4,106 to 2,126, p = .0021) in the RLAI group.
25. Fuller et al., 2009, the United States	Pre- and post-study	N = 106 Age = 51.9 years Male = 93.0% Aripiprazole, Olanzapine, Quetiapine, Risperidone, Ziprasidone, vs. RLAI	Psychiatric-related hospitalizations Number of psychiatric-related inpatient hospital days	6 months	Compared to the pre-RLAT period, the percentage of patients experiencing one or more psychiatric-related hospitalizations was significantly lower in the post-RLAT period (from 75% to 42%, p < .001). The total number of psychiatric-related inpatient hospital days decreased in the post-RLAT period (from 45 to 20 days, p < .001).
26. Beauclair et al., 2007*, Canada	Retrospective study	N = 69 Age = NA Male = NA Pre- vs. post-Risperidone Long-Acting Injectable (RLAI)	Psychiatric-related hospitalization Hospitalization days Number of hospitalizations	40 months	There were significant differences in hospitalization pre- and post-RLAI therapy, and fewer patients were hospitalized (from 50.7% pre-RLAI to 4.3% during RLAI treatment, p < .0001). The total duration of hospitalization days decreased by 99% (from 1,620 to 23, p < .0001). Fewer patients had more than one hospitalization (from 15.0% to 0.0%, p < .0001). The number of hospitalizations per patient decreased (from 0.81 to 0.04, p < .0001).
27. Bourin et al., 1998, France	Pre- and post-study	N = 48 Age = NA Male = NA Standard Neuroleptic (SN, n = 48) vs. Depot Neuroleptic (DN, n = 44) (RLAI)	Number of hospitalizations Total duration/patient/year	5 years	There was increased in the hospitalizations number when patients switched from SN to DN (from 4.8± 2.3 vs. 7.2 ± 3.7, p < .05). Total duration of hospitalization/ patient/year increased (5.2 ± 2.8 vs. 5.8 ± 3.2, p = na).
28. Tan, Ong, & Chee, 1981, Singapore	Pre- and post-study	N = 127 Age (15–65) = 32.5% Male = 61.4% Pre- vs. post-Fluphenazine decanoate (Modecate) depot therapy	Frequency of admission Length of hospitalization	24 months	Compared to the pre-Modecate therapy period, 105 patients showed a significant reduction of the number of admissions (from 139 to 78, p < .01). Compared to the pre-Modecate therapy period, the length of hospitalization decreased (from 4,377 days to 1,422 days, p < .01).
29. Polonowita & James, 1976, New Zealand	Pre- and post-study	N = 35 Age = NA Male = NA Pre- vs. post-Long-Acting Injections (LAI) Fluphenazine Decanoate	Number of admissions Hospital days number	13.4 months	Compared to the pre-LAI Fluphenazine Decanoate treatment period, patients had fewer readmissions in the post—LAI Fluphenazine Decanoate treatment period (from 60 to 22, p < .004). Compared to the pre-LAI Fluphenazine Decanoate treatment period, the mean length of hospitalization was less in the post-LAI Fluphenazine Decanoate treatment period (from 1,463 days to 327 days, p < .00005).
30. Johnson & Freeman, 1972,	Pre- and post study	N = 126 Age = 40.1 years Male = 78.0% Oral vs. Long-Acting Phenothiazines (L.A.P.)	Number of readmissions Length of hospital stay	12 months	Compared to the pre-L.A.P. treatment, the number of readmissions was reduced in post-L.A.P. treatment (from 100 to 57, p = na). Compared to the pre-L.A.P. treatment, the time of hospital care was reduced in post-L.A.P. treatment (from 5,843 days to 2,755 days, p = na).
31. Denham & Adamson, 1973, the United Kingdom	Pre- and post-study	N = 103 Age = 38.5 years Male = 57.0% Oral vs. Long-Acting Phenothiazines (Fluphenazine Enanthate and Decanoate)	Number of readmissions Duration of admissions	12 months	Compared to the pre-Long-Acting Phenothiazines treatment, the number of readmissions was reduced in post-Long-Acting Phenothiazines treatment (from 191 to 50, p = na). Compared to the pre-Long-Acting Phenothiazines treatment, duration of admissions was reduced in post-Long-Acting Phenothiazines treatment (from 8,713 days to 1,335 days, p = na).
32. Kamat et al., 2015, the United States	Retrospective study	N = 3,094 Age = 38.7 years Male = 55.0% Fluphenazine, Haloperidol, Paliperidone, Risperidone vs. long-acting injectable (LAI) antipsychotic	Mean number of hospitalizations Mean number of hospitalization days	12 months	Compared to the pre-LAI initiation, the mean number of hospitalizations reduced in post-LAI initiation (from 1.38 ± 2.19 to 1.08 ± 1.97, p < .0001). Compared to the pre-LAI initiation, the mean number of hospitalization days decreased in post-LAI initiation (from 11.52 ± 20.33 to 7.95 ± 19.72, p < .0001).
33. Lee et al., 2020, South Korean	Pre- and post-study	N = 1,272 Age = 44.2 years Male = 44.0% Oral Antipsychotics, (Benztropine, Procyclidine, and Propranolol) vs. LAI-PP	Hospitalizations/ admission days	12 months	Compared to the pre-PP period, the mean number of admissions days significantly decreased in the post-PP period (from 54.30 ± 61.93 to 29.75 ± 60.63, p < .0001).
34. Zhdanava et al., 2021	Retrospective study	N = 1,725 Age = 39.5 years Male = 56.9% Oral Antipsychotic vs. PP1M	Day spent in inpatients setting	12 months	Compared to the pre-PP1M period, there were significant reductions in the mean number of days spent in inpatient settings in the post-PP1M period (from 2.25 ± 2.95 to 1.56 ± 3.48, p < .01).
35. Ma et al., 2020, Germany	Pre- and post-study	N = 850 Age = 45.0 years Male = 54.6% Oral medication vs. LAI antipsychotics	Days spent in hospitals	12 months	The days spent in hospitals decreased from 73 to 59 days, p = na.
36. Patel, El Khoury, et al., 2020, the United States	Retrospective study	N = 493 Age = 52.0 years Male = 91.3% Risperidone or Paliperidone vs. PP1M	All-cause inpatient stays Number of MH-related and schizophrenia-related Number of inpatient stays for MH-related and schizophrenia-related Inpatient length of stay	12 months	The number of all-cause inpatient stays was significantly reduced from pre- to post-PP1M switch (from 2.3 to 1.0; p < .05), with a shorter length of stay (from 28.1 to 14.0 days; p < .05) post-PP1M switch. There were decreased in the number of MH-related (from 1.5 to 0.8; p < .05) and schizophrenia-related (from 0.6 to 0.3; p < .05) inpatient stays, and for MH-related (from 27.1 to 13.8 days; p < .05) and schizophrenia-related (from 13.2 to 5.7 days; p < .05) inpatient length of stay.
Outpatient visits
1. Fefeu et al., 2018, the United States	Retrospective study	N = 40 Age = 42.6 years Male = 67.5% Oral Olanzapine vs. OLAIs	Number of outpatient visits	12 months	There was no difference in the mean number of outpatient visits between pre- and post-initiation of the OLAIs (7.25 ± 5.66 vs. 7.95 ± 5.01, p = .49).
2. Patel, Emond, et al., 2020, the United States	Retrospective study	N = 427 Age = 41.1 years Male = 62.1% Oral Risperidone or Oral Paliperidone vs. PP1M	Number of outpatient visits	6 months	Patients had a similar number of mental-health-related outpatient visits per month before and after the switching to PP1M (3.26 ± 5.82 vs. 3.53 ± 6.18, p = .072).
3. Chang et al., 2012, Taiwan	Pre- and post-study	N = 184 16–35 years old = 31.0% 36–55 years old = 60.3% 56 years and over = 8.7% Male = 50.5% From Oral Antipsychotics to RLAI	Number of outpatient visits	12 months	Compared to the pre-RLAI period, the total annual number of outpatient service uses increased by 48.5% in the post-RLAI period (from 2,493 to 3,701, p < .0001).
4. Ren et al., 2011, the United States	Pre- and post-study	N = 924 Age = 51.4 years Male = 93.6% Pre- vs. Post RLAT	Number of outpatient visits	12 months	Compared to the pre-initiation period, the mean number of outpatient visits increased during the post-initiation period (from 25 to 39; p < .0001).
5. Fuller et al., 2009, the United States	Pre- and post study	N = 106 Age = 51.9 years Male = 93.0% Aripiprazole, Olanzapine, Quetiapine, Risperidone, Ziprasidone, vs. RLAI	Number of outpatient visits	6 months	The number of psychiatric-related outpatient visits increased in the post-RLAT period (mean change 1.0 ± 2.8 visit, p < .001).
6. Lee et al., 2020, South Korean	Pre- and post-study	N = 1,272 Age = 44.2 years Male = 44.0% Oral Antipsychotics, (Benztropine, Procyclidine, and Propranolol) vs. LAI-PP	Number of outpatient visits/days	12 months	Compared to the pre-PP period, the mean number of outpatient visits/days significantly decreased in the post-PP period (from 199.06 ± 134.03 to 332.51 ± 59.30, p < .0001).
7. Zhdanava et al., 2021	Retrospective study	N = 1,725 Age = 39.5 years Male = 56.9% Oral Antipsychotic vs. PP1M	Number of outpatient visits	12 months	Compared to the pre-PP1M period, there were reductions in the mean number of outpatient visits in the post-PP1M period (from 1.20 ± 1.57 to 1.13 ±1.32 p < .068).
8. Patel, El Khoury, et al., 2020, the United States	Retrospective study	N = 493 Age = 52.0 years Male = 91.3% Risperidone or Paliperidone vs. PP1M	Number of outpatient visits	12 months	There was an increase in the total number of all-cause outpatient visits (from 47.6 to 54.6; p < .05).
Emergency department (ED)
1. Hsia et al., 2017, the United States	Pre-post study	N = 75 Age = 48.5 years Male = 90.7% Oral Risperidone vs. Paliperidone Long-Acting Injectable (LAI)	Number of EDs	6 months	Switching from oral risperidone to paliperidone LAI was associated with significant decreases in the number of ED/mental health urgent care visits (from 1.0 to 0.0, p < .001).
2. Leal et al., 2004, Austria, Canada, the Czech Republic, Denmark, France, Germany, the Netherlands, Norway, Poland, Sweden, Switzerland, and the United Kingdom	Prospective study	N = 397 Age = 43.6 years Male = 63.0% Oral Risperidone vs. Long-Acting Risperidone	Rate of ED visits	12 weeks	The percentage of patients requiring ED visits decreased from the 12 weeks pre-Long-Acting Risperidone to the 12 weeks post-Long-Acting Risperidone (from 3.0% to 1.0%, p = na).
3. Koczerginski, & Arshoff, 2011, Canada	Retrospective study	N = 25 Age = na Male = na Oral therapy vs. Long-Acting Risperidone (RLAI)	Number of EDs Length of stay in ED	12 months	There were significant decreases in the rate of ED visits from the pre- to post-RLAI treatment period (from 2.2 to 0.4, p = .0001). There were significant reductions in the rate of total average length of stay in the ED from the pre- to post-RLAI period (from 1.2 to 0.1; p < .0001).
4. Patel, Emond, et al., 2020, the United States	Retrospective study	N = 427 Age = 41.1 years Male = 62.1% Oral Risperidone or Oral Paliperidone vs. PP1M	Number of ED visits	6 months	There were significant reductions in the mean number of ED visits from the pre- to post-PP1M period (from 0.32 ± 0.58 to 0.22, ± 0.50, p < .001).
5. Chang et al., 2012, Taiwan	Pre- and post-study	N = 184 16–35 years old = 31.0% 36–55 years old = 60.3% 56 years and over = 8.7% Male = 50.5% From Oral Antipsychotics to RLAI	Number of ED visits	12 months	There were reductions in the number of ED visits from pre-to post-RLAI period (from 107 to 61, p = .09).
6. Crivera et al., 2011, the United States	Prospective study	N = 435 Age = 41.9 years Male = 66.7% Pre- vs. Post-RLAT	Number of ED visits	12 months	There were reductions in the mean number of ED visits from pre- to post-initiation of RLAT (from 0.65 to 0.39, p < .01).
7. Su et al., 2009, Taiwan	Pre- and post-study	N = 108 Age = 42.0 years Male = NA Oral Risperidone, FGAs, or SGAs vs. RLAI	Number of ED visits	12 months	There were reductions in the number of ED visits from pre-to post-RLAI period (from 55 to 25, p = .125).
8. Zhdanava et al., 2021	Retrospective study	N = 1,725 Age = 39.5 years Male = 56.9% Oral Antipsychotic vs. PP1M	ED visits	12 months	There were significant reductions in the mean number of ED visits from pre- to post-PP1M period (from 0.27 ± 0.53 to 0.23 ± 0.71, p < .028).
Health care utilization
1. Fefeu et al., 2018, the United States	Retrospective study	N = 136 Age = 42.7 years Male = 67.5% Oral Olanzapine vs. OLAIs	Inpatient service cost	12 months	There was 86.2% reduction in the cost of inpatient service after the initiation of the OLAIs (from 48,024 ± 43,434€ to. 6,603 ± 13,066€, p < .0001).
2. Patel, Emond, et al., 2020, the United States	Retrospective study	N = 427 Age = 41.1 years Male = 62.1% Oral Risperidone or Oral Paliperidone vs. PP1M	Health care costs (medical and pharmacy)	6 months	Compared to pre-PP1M switch, there were decreases in all-cause inpatient stay costs (from $41,886 to $20,489; p < .05) and increases in outpatient visit costs (from $22,005 to $29,069; p < .05) in post-PP1M switch. After the switch to PP1M, total medical costs decreased from $63,871 to $49,558 (p < .05). Pharmacy costs increased post-PP1M (MMCD = $960, p < .001), but were offset by decreasing all-cause medical costs (MMCD = − $732, p < .001).
3. Willis et al., 2010, Sweden	Retrospective study	N = 77 Age = 44.7 years Male = 57.0% Atypical Oral Antipsychotic vs. Risperdal Consta	Annual hospital costs and medication costs	12 months	Mean annual hospital costs per year per patient significantly decreased from 157,374 to 105,107, (p = .012). Mean annual medicine costs per year per patient significantly increased from 9,053 to 14,804, (p = .007).
4. Olivares et al., 2008, Spain	Retrospective and prospective study	N = 788 Age = 39.3 years Male = 61.5% Pre- vs. Post-Long-Acting Injectable Risperidone	Medication costs Hospitalization costs	12 months 24 months	There was an increase in medication cost per month compared with previous oral antipsychotic medication after 12 months (from €128.16 to €405.80, p = na) and 24 months (from €142.77 to €407.33, p = na). There was a reduced hospitalization cost per month compared with previous antipsychotic medication after 12 months (from €335.91 to €61.44, p = na) and 24 months (from €446.25 to €52.62, p = na).
5. Chang et al., 2012, Taiwan	Pre- and post-study	N = 184 16–35 years old = 31.0% 36–55 years old = 60.3% 56 years and over = 8.7% Male = 50.5% From Oral Antipsychotics to RLAI	Costs (outpatient, emergency and inpatient psychiatric service costs, medication, and non-medication costs)	12 months	In the post-RLAI period, psychiatric service costs per person were increased by 25.6% (from $37.7, 95% CI = [20.5, 57.1], p < .0001), total outpatient service costs increased by 190.3% ($74.6, 95% CI = [66.7, 82.6], p < .0001), and total inpatient service costs decreased by 34.1% ($36.7, 95% CI = [−57.2, −14.4], p < .005). The emergency service costs remained unchanged after switching to RLAI treatment −25.0% (from $−0.1, 95% CI = [−0.5, −0.2], p = .48). The medication costs were increased by 177.1% (from $72.0 [95% CI = 66.8 to 77.0], p < .0001), and the non-medication decreased by 32.1% ($34.2, 95% CI = [−51.2, −16.6], p < .001).
6. Peng et al., 2011, the United States	Pre- and post-study	N = 147 Age = 42.6 years Male = 53.7% Pre- vs. Post-RLAT	Hospitalization cost	6 months	Total health care costs decreased from $11,111 to $7,884 (p < .05) driven by reductions in psychiatric hospitalization costs from $5,384 to $2,538 (p < .05).
7. Fuller et al., 2009, the United States	Pre- and post-study	N = 106 Age = 51.9 years Male = 93.0% Aripiprazole, Olanzapine, Quetiapine, Risperidone, Ziprasidone, vs. RLAI	Mean monthly costs (medication costs, hospitalization costs, and outpatient visit costs)	6 months	Monthly psychiatric-related medication costs increased by $356 ± $214, (p < .001). Monthly hospitalization costs decreased by $2,273 ± $5,450 (p < .001), monthly outpatient visits costs increased by $320 ± $1,355 (p = .02).
8. Kamat et al., 2015, the United States	Retrospective study	N = 3,094 Age = 38.7 years Male = 55.0% Fluphenazine, Haloperidol, Paliperidone, Risperidone vs. LAI antipsychotic	Mean number of hospitalization days Medical costs	12 months	Compared to the pre-LAI initiation, the mean reduction in medical costs was $3.599, p < .0001 in post-LAI initiation.
9. Lee et al., 2020, South Korean	Pre- and post-study	N = 1,272 Age = 44.2 years Male = 44.0% Oral Antipsychotics, (Benztropine, Procyclidine, and Propranolol) vs. LAI-PP	Outpatient and admission costs	12 months	Compared to the pre-PP period, there were reductions in mean number of outpatient costs (from 1,505.22 ± 1,353.27 to 3,002.37 ± 1,217.12, p < .0001) and admission costs (2,969.53 ± 3,587.37 to 1,748.78 ± 3,639.64, p < .0001) in the post-PP period.
10. Zhdanava et al., 2021	Retrospective study	N = 1,725 Age = 39.5 years Male = 56.9% Oral antipsychotic vs. PP1M	Health care costs	12 months	Compared to the pre-PP1M period, the pharmacy costs increased by $514 and medical costs decreased by $391, p < .01 in the post-PP1M period.
11. Mahlich et al., 2020, Germany	Pre- and post-study	N = 850 Age = 45.0 years Male = 54.6% Oral Medication vs. LAI Antipsychotics	Annual treatment costs Hospitalization costs Outpatient costs	12 months	The total annual treatment costs were reduced from 13,776 euros in pre-index period to 10,418 euros after LAI initiation, p = na. There was decreases in hospitalization costs (from 11,908 euros to 5,345 euros), p = na. Costs for outpatient service increased from 581 euros to 789 euros, p = na.
12. Patel, El Khoury, et al., 2020, the United States	Retrospective study	N = 493 Age = 52.0 years Male = 91.3% Risperidone or Paliperidone vs. PP1M	All-cause inpatient stays costs Outpatients visit costs (medical and pharmacy costs) All-cause total costs MH-related costs and the total schizophrenia-related costs	12 months	There were decreases in all-cause inpatient stay costs ($41,886 vs. $20,489; p < .05) and increases in outpatient visit costs ($22,005 vs. $29,069; p < .05). Total medical costs were lower after the switch (decreasing from $63,871 to $49,558; p < .05), but outpatient pharmacy costs increased from pre- to post-PP1M switch ($3,109 vs. $12,112; p < .05). All-cause total costs (inpatient, outpatient, and pharmacy costs) decreased from $66,980 to $61,670 (p = .8638) between pre- and post-PP1M switch. The total MH-related costs decreased from $61,978 to $55,786 (p = .7640) and the total schizophrenia-related costs increased from $30,108 to $31,904 (p < .05), respectively, between pre- and post-PP1M switch.
Personal and Social Performance (PSP)
1. Kwon et al., 2015, Korea	RCT	N = 134 Age = 34.3 years Male = 50.4% Oral Antipsychotics vs. LAI Immediate switch group = 67 Delayed switch group = 67	PSP	21 weeks	Both groups showed significant increases in the total PSP from baseline to final visit (immediate switch group = 60.6 ± 14.4 vs. 64.1 ± 11.3, p = .027 delayed switch group = 60 ± 12.8 vs. 63.4 ± 14.1, p = .013).
2. Emsley et al., 2017, Croatia, Italy, Russia, and Turkey	Retrospective study	N = 84 Age = 24.1 years Male = 69.0% Oral Antipsychotic (n = 45) vs. PP1M (n = 45)	PSP	12 months	There were improvements in mean PSP from baseline (52.1) to endpoint (64.0), the mean change was 11.9 ± 15.0; p < .001.
3. Li et al., 2019, Asian patients from China, Hong Kong, Korea, Malaysia, Philippine s, Taiwan, and Thailand	Prospective study	N = 121 Age = 36.2 years Male = 59.5% Tolerability to oral paliperidone or oral risperidone was performed ≤ 1 week before initiating PP1M, n = 121 Oral Antipsychotics vs. PP1M	PSP	13 months	The mean total PSP significantly improvement from baseline to week 13 (43.8 ± 12.27 vs. 19.8 ± 16.50, p ≤ .0001).
4. Devrimci-Ozguven et al., 2019, Finland	Retrospective study	N = 222 Age = 38.5 years Male = 57.0% Oral PP vs. PP injection	PSP	12 months	Compared to the period before PP injections, the median of PSP during PP injections treatment was significantly improved (from 37.5 ± 15–70 to 70.5 ± 22–85, p < .001).
5. Si et al., 2016, China	Prospective study	N = 610 Age = 31.3 years Male = 60.5% Oral Antipsychotic (risperidone/paliperidone ER, n = 263; Olanzapine, n = 52; other antipsychotics, n = 293) vs. PP1M	PSP	13 weeks	After switching to PP1M, patients showed significant improvements on the mean PSP scores from baseline to the endpoint for risperidone/paliperidone ER (from 19.5 ± 15.9 to 45 ± 13.6, p < .001), olanzapine (from 17.1 ± 17.2 to 43.8 ± 14.2, p < .001), and other antipsychotics (from 19.6 ± 16.5 to 44.9 ± 13.6, p < .001).

Data for the meta-analysis was derived from an abstract presentation with the following citation: Beauclair et al. (2005).

Rehospitalization

All except one (Bourin et al., 1998) of the 36 studies that reported rehospitalizations found a decrease in the number of rehospitalizations after switching to an LAI (Table 1).

Outpatient and ED Visits

Eight studies reported the number of outpatient visits pre- and post-LAI initiation (Table 1). Two studies showed no differences (Fefeu et al., 2018; Patel, Emond, et al., 2020), while two showed decreases in the number of outpatient visits (Lee et al., 2020; Zhdanava et al., 2021). However, four studies showed an increase in the number of outpatient visits/claims between pre- and post-LAI initiation (Chang et al., 2012; Fuller et al., 2009; Patel, El Khoury, et al., 2020; Ren et al., 2011). Also, five (Crivera et al., 2011; Hsia et al., 2017; Koczerginski & Arshoff, 2011; Patel, Emond, et al., 2020; Zhdanava et al., 2021) of eight studies reported significant reductions in the number of ED visits upon initiation of LAIs (Table 1).

Health Care Costs

Twelve studies compared the health care costs pre- and post-LAI initiation (Table 1). Ten studies reported reductions in overall health care costs after LAI initiation (Fefeu et al., 2018; Kamat et al., 2015; Lee et al., 2020; Mahlich et al., 2020; Olivares et al., 2008; Patel, El Khoury, et al., 2020; Patel, Emond, et al., 2020; Peng et al., 2011; Willis et al., 2010; Zhdanava et al., 2021). However, after switching to LAIs, six studies reported an increase in pharmacy costs (Chang et al., 2012; Fuller et al., 2009; Olivares et al., 2008; Patel, Emond, et al., 2020; Willis et al., 2010; Zhdanava et al., 2021), four studies found increases in outpatient costs (Chang et al., 2012; Fuller et al., 2009; Mahlich et al., 2020; Patel, Emond, et al., 2020), and one study found a decrease in the outpatient costs (Lee et al., 2020) (Table 1).

Social Functioning

Four of five studies showed significant improvements in PSP scores from the oral to the LAI treatment period (Devrimci-Ozguven et al., 2019; Emsley et al., 2017; Kwon et al., 2015; Li et al., 2019; Si et al., 2016) (Table 1).

Meta-Analysis

Meta-analyses were conducted to pool the results of studies on symptom remission, rehospitalizations, outpatient and ED visits, and social functioning. Heterogeneity varied across models; therefore, a random effects model was used. Studies that provided data related to health care costs used different statistical approaches. Thus, the pooled effect size could not be calculated.

Symptom Remission

The pooled analysis of the studies showed LAIs were superior in decreasing the PANSS score compared to the oral antipsychotic treatment period (n = 2,622, effect size = −0.225, 95% CIs = [−0.286, −0.164], p < .001; I² = 50.52%, p = .033) (Figure 1). Also, the forest plot showed significant differences in the mean CGI score when switching from oral to LAI (n = 2,319, effect size = −0.262, 95% CIs = [−0.335, −0.188], p < .001; I² = 60.755%, p = .006) (Figure 2). The effect size for mean GAF scores could not be calculated because the studies varied widely in the statistical approaches to analyzing this outcome.

Figure 1.

Forest Plot of the Change Between LAIs and Orals in the Mean PANSS Score.

Figure 2.

Forest Plot of the Change Between LAIs and Orals in the Mean CGI Score.

Rehospitalization

The forest plot showed a significant reduction in the mean number of rehospitalizations when patients switched from an oral to LAI antipsychotic (n = 5,038, effect size = −0.224, 95% CIs = [−0.318, −0.131], p < .001; I² = 82.10%, p < .001) (Figure 3).

Figure 3

Forest Plot of the Changes Between LAIs and Orals in the Mean Number of Rehospitalizations.

Outpatient and ED Visits

We calculated the pooled effect size of switching from oral to LAI on the mean number of ED visits for only five of eight studies that used similar statistical approaches for outpatient visits. The pooled analysis of these five studies found no differences in switching from oral to LAI on the mean number of outpatient visits (n = 3,570, effect size = −0.022, 95% CIs = [−0.112 to 0.068], p < .628; I² = 78.769%, p < .001) (Figure 4). However, the pooled effect size of switching from oral to LAI on the mean number of ED visits was not calculated because these studies used different statistical approaches.

Figure 4.

Forest Plot of the Changes Between LAIs and Orals in the Mean Number of Outpatient Visits.

Social Functioning

Four studies found that switching from an oral to LAI antipsychotic resulted in significantly increased PSP mean scores (n = 2,892, effect size = 0.432, 95% CIs = [0.324, 0.539], p < .001; I² = 0.00%, p < .001) (Figure 5).

Figure 5.

Forest Plot of the Changes Between LAIs and Orals in the Mean PSP Score.

Publication Bias

We used funnel plots, Egger’s regression test, and Duval and Tweedie’s trim and fill methods to assess publication bias. The PANSS, CGI, and rehospitalizations outcomes were reported in at least 10 studies; therefore, publication bias for these outcomes was evaluated. The three funnel plots were asymmetrical. The effect sizes were somewhat altered after applying the trim and fill procedure to correct for any publishing biases. The point estimate for the PANSS was −0.16476 (95% CIs = [−0.23367, −0.09584]), the CGI was −0.20394 (95% CIs = [−0.27612, −0.13176]), and the rehospitalizations were −0.18050 (95% CIs = [−0.26848, to −0.09252]). Hence, these results suggested little evidence for publication bias.

Discussion

The purpose of this systematic review was to synthesize the evidence regarding the effect of switching from oral to LAI antipsychotics on patient outcomes. Our findings, indicating that switching from an oral to LAI resulted in greater symptom remission (PANSS, CGI, and GAF), are similar to the results of a recent meta-analysis (Kishimoto et al., 2021) and are supported by new additional studies (Lee, 2021; Strunoiu et al., 2021). Recent studies indicate that patients might experience symptom improvement associated with LAI use as a result of improved medication adherence (Kishimoto et al., 2021; Okoli et al., 2022). Similarly, the greater reductions in rehospitalizations and ED visits and improvements in social functioning because of switching to LAIs might also be enhanced by improved medication adherence (Lin et al., 2021; Magliocco et al., 2020). Thus, these findings lend support for switching to LAIs when indicated to support recovery among those with schizophrenia.

In addition, our findings demonstrated that switching to LAIs was linked to lower overall medical care costs compared to treatment with oral antipsychotics. However, pharmacy costs increased after switching to LAIs. In a recent meta-analysis of U.S. studies, Lin et al. (2021) similarly reported increases in pharmacy costs after switching from an oral to an LAI. However, the study also found decreases in rehospitalizations and overall medical care costs. In other words, although switching to LAIs may result in increased pharmacy-related costs, these costs might be offset by overall lower medical costs. Hence, taken together, switching to LAIs might have an additional benefit of reduced health care utilization apart from pharmacy costs.

The present findings have some limitations. First, the effect of changing antipsychotic administration route on patient adherence outcomes was not investigated in this study because few studies have reported this phenomenon. Second, the types of LAIs and oral antipsychotics were different (e.g., first-generation vs. second-generation) in most of the included studies. Thus, future studies may examine the effect of switching between specific antipsychotic types on clinical outcomes. Third, this review could not account for variations in patient characteristics or clinical settings prior to and after switching to an LAI, which might have introduced biases affecting our primary outcomes.

Despite the limitations inherent in the studies included in our review, we found that changing antipsychotic administration route can be beneficial for clinical, quality of life, and health care utilization outcomes among people with schizophrenia spectrum disorder. Total pharmacy costs may increase, but this increase may be offset by decreases in medical care costs and fewer rehospitalizations. Future research is needed to examine the effectiveness of changing antipsychotic administration route on adherence, as well as ways to improve accessibility while lowering pharmacy costs. Such studies will provide evidence to support clinical outcomes associated with treatment for schizophrenia.

Implications for Practice

Mental health providers who have the authority to prescribe treatment should clearly communicate with patients and caregivers about the risks of long-acting injectable antipsychotic medications, for example, pain at injection site, extrapyramidal side effects, and weight gain. Also, mental health providers should discuss the benefits of switching to LAIs as part of evidence-based decision-making, for instance, decreased frequency of medication administration, lower risks of rehospitalization, and improved quality of life.

Conclusion

The outcomes of this systematic review demonstrated that after switching to an LAI, patients with schizophrenia spectrum disorder may experience improvements in clinical, quality of life, and health care utilization outcomes. However, there were inconsistencies in the findings related to changes in outpatient visits. Moreover, half of the reviewed studies reported increases in pharmacy costs following the switch to an LAI. In addition, the findings that switching from an oral to an LAI improved symptom remission, social functioning, and decreased rehospitalizations were supported by the pooled analysis. These findings are important in guiding future research and informing evidence-based practice related to the use of antipsychotics for patients with schizophrenia spectrum disorder.

Supplemental Material

sj-pdf-1-jap-10.1177_10783903241279605 – Supplemental material for Clinical, Quality of Life, and Health Care Utilization Outcomes of Switching the Administration Route of Antipsychotic Medications Among People With Schizophrenia Spectrum Disorder: A Systematic Review and Meta-Analysis

Supplemental material, sj-pdf-1-jap-10.1177_10783903241279605 for Clinical, Quality of Life, and Health Care Utilization Outcomes of Switching the Administration Route of Antipsychotic Medications Among People With Schizophrenia Spectrum Disorder: A Systematic Review and Meta-Analysis by Amani Kappi, Tianyi Wang, Bassema Abu farsakh and Chizimuzo T. C. Okoli in Journal of the American Psychiatric Nurses Association

Footnotes

Author Roles

All authors contributed to the conception or design of the study or to the acquisition, analysis, or interpretation of the data. All authors drafted the manuscript, or critically revised the manuscript, and gave final approval of the version that was submitted for publication. All authors agree to be accountable for all aspects of the work, ensuring integrity and accuracy.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research reported in this publication was supported, in part, by the Cabinet for Health and Family Services, Department for Medicaid Services under Agreement titled “Assessing the Impact of Long-Acting Injectables on Psychiatric Treatment Outcomes among Medicaid Beneficiaries.”

ORCID iDs

Amani Kappi

Chizimuzo T. C. Okoli

Supplemental Material

Supplemental material for this article is available online.

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