# Impact of long-acting injectable antipsychotics in early psychosis: An umbrella review

Marie Etienne, Helene Verdoux

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Marie Etienne, Helene Verdoux. Impact of long-acting injectable antipsychotics in early psychosis: An umbrella review. Schizophrenia Research, 2025, 277, pp.140-150. 10.1016/j.schres.2025.03.002. hal-05007075

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# Impact of long-acting injectable antipsychotics in early psychosis: An umbrella review

Marie Etienne<sup>a,b</sup>, Hélène Verdoux<sup>a,*</sup>

## ARTICLE INFO

**Keywords:**

First-episode psychosis

Early psychosis

Long-acting injectable antipsychotics

Umbrella review

## ABSTRACT

**Objectives:** There is still no consensus regarding the indications of long-acting injectable antipsychotics (LAIs) in early psychosis (EP). This umbrella review synthesizes findings from systematic reviews and meta-analyses on the risk-benefit balance of LAIs in EP.

**Methods:** Eligible systematic reviews and meta-analyses on LAIs in EP were identified by a MEDLINE search from inception until June 2024. Data were synthesized narratively.

**Results:** Seven systematic reviews and four meta-analyses published from 2007 to 2024 were identified. They included 220 to 14,313 participants recruited in 58 primary unique randomized controlled trials or observational studies. All LAIs were considered in most reviews. Inclusion criteria and diagnoses differed widely across the selected reviews. The reviews and meta-analyses consistently showed a positive impact of LAIs on symptomatic outcome in people with EP, although there was no consensus on whether LAIs outperformed oral anti-psychotics (OAPs). Most reported a greater reduction of treatment discontinuation due to inefficacy or nonadherence with LAIs vs. OAPs, although meta-analyses found no difference between LAIs vs. OAPs regarding all-cause discontinuation. Findings regarding relapse prevention were inconclusive. Similar rates of metabolic adverse drug reaction and potentially lower rates of extrapyramidal symptoms were observed with LAIs vs. OAPs.

**Conclusion:** LAIs should be considered according to users' preferences and could be particularly useful for people with a poor medication adherence risk profile. Further high-quality observational studies in real-life prescribing conditions are needed to support robust recommendations for clinical practice regarding indications of LAIs in EP.

## 1. Introduction

First-episode psychosis (FEP) typically occurs in adolescence or early adulthood, a pivotal period in personal and professional life (Lian et al., 2022b; Solmi et al., 2022a). This phase is critical for treatment management since medication non-adherence after an FEP is the main predictor of the first relapse (Alvarez-Jimenez et al., 2012; Pelayo-Terán et al., 2017).

Long-acting injectable antipsychotics (LAIs) were developed to minimize the treatment discontinuation frequently observed with oral antipsychotics (OAPs) (Khan et al., 2016; Ostuzzi et al., 2021). Evidence from recent studies suggested that they have a positive prognostic impact in schizophrenia patients with a lower risk of rehospitalization, relapse, discontinuation and treatment failure compared to OAPs (Hamina et al., 2024; Kishimoto et al., 2021; Tiihonen et al., 2017;

Verdoux et al., 2017) or placebo (Ostuzzi et al., 2021). Nonetheless, inconsistent results were found by meta-analyses showing no advantage of LAIs over OAPs regarding relapse reduction (Kishimoto et al., 2014), hospitalization risk (Kishimoto et al., 2018), drop out for any reason (Ostuzzi et al., 2017) and higher rates of extrapyramidal syndrome and prolactin-related symptoms (Park et al., 2018). In this context, they are still predominantly prescribed for people with chronic schizophrenia with a poor outcome profile, i.e. who are non-adherent and have experienced multiple relapses (Khan et al., 2016).

Promising evidence from systematic reviews and meta-analyses of both RCTs and observational studies suggest that LAIs may be more beneficial to people with early psychosis (EP) than OAPs (Emsley et al., 2013; Lian et al., 2022a, 2022b; Salgueiro and Segarra, 2019; Taylor and Ng, 2013; Zhornitsky and Stip, 2012) or periods without LAIs (Emsley et al., 2013; Lian et al., 2022a; Salgueiro and Segarra, 2019; Taylor and

<footnote><sup>a</sup> Univ. Bordeaux, Inserm, Bordeaux Population Health Research Center, team pharmacoepidemiology, UMR 1219, F-33000 Bordeaux, France</footnote>

<footnote><sup>b</sup> Centre Hospitalier Charles Perrens, F-33000 Bordeaux, France</footnote>

<footnote>* Corresponding author at: University Bordeaux, UMR 1219, Case 36, 146 Rue Léo Saignat, 33076 Bordeaux Cedex, France.</footnote>

<footnote>E-mail address: helene.verdoux@u-bordeaux.fr (H. Verdoux).</footnote>
Ng, 2013). Their impact is particularly positive in preventing relapse and hospitalization (Lian et al., 2022a, 2022b; Salgueiro and Segarra, 2019; Taylor and Ng, 2013; Zhornitsky and Stip, 2012) by improving symptoms control (Lian et al., 2022a; Salgueiro and Segarra, 2019; Taylor and Ng, 2013) and enhancing medication adherence (Lian et al., 2022a; Salgueiro and Segarra, 2019). However, two meta-analyses of RCTs reported contradictory results, showing no advantage of LAIs over OAPs in relapse and all-cause discontinuation rates (Kishi et al., 2016; Vita et al., 2024). Many of these prior reviews emphasized the need for more robust evidence from high-quality trials (Emsley et al., 2013; Kishi et al., 2016; Lian et al., 2022a, 2022b; Salgueiro and Segarra, 2019; Taylor and Ng, 2013; Vita et al., 2024). The lack of agreement has resulted in heterogenous recommendations on this specific topic, with as yet no consensus regarding the risk-benefit balance of LAIs in EP (Correll et al., 2022a).

A comprehensive review of the literature is therefore needed to
provide further evidence of the potential benefits of LAIs in people with
EP. An umbrella review may provide a broader synthesis of the current
knowledge by highlighting the consistencies and contradictions of prior
findings. Identifying the main consensual benefits of LAIs in EP might
support the development of clinical practice guidelines. The aim of the
present umbrella review was to synthesize findings from systematic re-
views and meta-analyses on the impact of LAIs treatment in EP
regarding the following outcomes: (i) efficacy and effectiveness, (ii)
adverse drug reactions, and (iii) the attitudes of both patients and cli-
nicians regarding this treatment approach.

2. Materials and methods

## 2.1. *Search strategy and eligibility criteria*

We performed a MEDLINE search from database inception until 8th June 2024 using the following search algorithm: “first episode psycho* OR first episode schizophrenia OR early schizophrenia OR early psy- cho*) AND (depot antipsychotic* OR long-acting injectable antipsy- chotic* OR LAIs)”. We examined articles published in English or in French. Systematic review and/or meta-analyses were considered eligible when they met the following criteria:

(i) Systematic reviews and/or meta-analyses including patients presenting with FEP, EP or a recent diagnosis of schizophrenia or schizophrenia spectrum disorders (i.e. schizophrenia, schizoaffective disorder, schizophreniform disorder, brief psychotic episode). The duration of illness defining FEP, EP and early schizophrenia was that used by each study's authors.

(ii) Systematic reviews and/or meta-analyses assessing the following outcomes regarding LAIs treatment, irrespective of the molecule: a) efficacy or effectiveness, assessed by symptomatic outcome, medication persistence, remission, relapse, or mortality; or b) adverse drug reactions (ADR); or c) patients' or clinicians' attitude towards LAIs prescription.

(iii) Systematic reviews and/or meta-analyses were included regardless of the criteria used for study selection: a) clinical trials: randomized-controlled trials (RCTs) and prospective non-randomized trials; b) observational studies: case-control studies, prospective or retrospective cohort studies, retrospective chart reviews and case reports.

We also examined manually related references from selected articles.
A review protocol was registered in the International Prospective Reg-
ister of Systematic Reviews (registration number CRD42024605420).
This umbrella review was conducted following the methodological
guidance provided by the Joanna Briggs Institute (Aromataris et al.,
2015).

## 2.2. Data extraction and quality assessment

Titles and abstracts of identified records were screened, selected full-
text articles were assessed for eligibility, and data were extracted
independently by two researchers (ME and HV); disagreement was
resolved by discussion. For each selected article, we extracted the
following information when available: (i) reference: first author's name,
year of publication; (ii) study type: systematic review and/or meta-
analysis; (iii) objectives; (iv) database(s) used, date of the research,
search algorithm when specified; (v) study selection, including a)
number of included studies, b) study design, c) date of publication, d)
number of patients, e) population and diagnoses, f) LAIs considered, g)
comparator when using OAPs, placebo or periods without LAIs; (vi)
mean follow-up duration when reported, or calculated mean follow-up
duration when not; (vii) outcome(s): psychotic symptoms and/or
illness severity evaluated by validated rating scale, treatment discon-
tinuation, medication adherence, remission, relapse, mortality, ADR,
and clinicians' opinion about this specific strategy; (viii) main findings
including statistical analyses when reported; (ix) limitations; (x) funding
and conflicts of interest. The data were synthesized narratively, since the
literature mostly includes narrative systematic reviews including qual-
itative information. The methodological quality of each included sys-
tematic review or meta-analysis was assessed by the two researchers
using the assessment tool AMSTAR-2 (A Measurement Tool to Assess
Systematic Reviews) (Shea et al., 2017) (supplementary Table 1). We
used the method developed by (Pieper et al., 2014) to quantify the de-
gree of publication overlap by calculating the corrected covered area
(Supplementary Table 2).

3. Results

3.1. *Literature search*

Fig. 1 presents the eligibility process for this umbrella review. Ulti-
mately, seven narrative systematic reviews (Emsley et al., 2013;
Kirschner et al., 2013; Lian et al., 2022a; Parellada, 2007; Salgueiro and
Segarra, 2019; Taylor and Ng, 2013; Zhornitsky and Stip, 2012) and four
systematic reviews and meta-analyses (Correll et al., 2022b; Kishi et al.,
2016; Lian et al., 2022b; Vita et al., 2024) published from 2007 to 2024
were selected (Table 1). Of the 58 original studies about LAIs use in EP
identified by prior reviews, between one (Correll et al., 2022b) and 33
(Lian et al., 2022a) original studies were included in each selected re-
view, with a mean number of included studies of 10 (SD 8.7). The
number of participants included in the reviews ranged from 220 to
14,313.

All selected reviews used at least two electronic databases to perform
their article selection. The designs of included studies varied from one
review to another: RCTs (N = 2) (Kishi et al., 2016; Vita et al., 2024);
RCTs and observational studies (N = 2) (Lian et al., 2022a, 2022b);
RCTs, observational studies and other study designs (N = 2) (Emsley
et al., 2013; Taylor and Ng, 2013); RCTs and non-randomized open label
trials (N = 1) (Salgueiro and Segarra, 2019); observational studies and
open-label trial (N = 1) (Zhornitsky and Stip, 2012); observational
studies (N = 1) (Correll et al., 2022b), open label trials (N = 1)
(Parellada, 2007) and review on attitudes based on cross-sectional sur-
veys (N = 1) (Kirschner et al., 2013).

Inclusion criteria about target population and diagnoses also differed
across selected reviews, most of them using several definitions (Sup-
plementary Table 3). The diagnoses considered were: FEP (N = 9)
(Emsley et al., 2013; Kirschner et al., 2013; Kishi et al., 2016; Lian et al.,
2022a, 2022b; Salgueiro and Segarra, 2019; Taylor and Ng, 2013; Vita
et al., 2024; Zhornitsky and Stip, 2012), EP (N = 3) (Emsley et al., 2013;
Lian et al., 2022a, 2022b), recent-onset psychotic disorder (N = 3) (Kishi
et al., 2016; Lian et al., 2022a, 2022b), schizophrenia or related disorder
with a mean duration of illness ≤5 years (N = 3) (Lian et al., 2022a,
2022b; Vita et al., 2024), early schizophrenia (N = 1) (Taylor and Ng,
<figure><img src="image_3.png" /><figcaption>Fig. 1. Flow diagram for study selection of reviews on long-acting injectable antipsychotics (LAIs) in early psychosis (EP).</figcaption></figure>

2013), first-episode schizophrenia (N = 1) (Parellada, 2007), and inci-
dent schizophrenia (N = 1) (Correll et al., 2022b). When specified, the
mean duration of illness was ≤2 years (N = 1) (Salgueiro and Segarra,
2019), ≤ 3 years (N = 4) (Lian et al., 2022b; Parellada, 2007; Taylor and
Ng, 2013; Vita et al., 2024) or ≤ 5 years (N = 3) (Emsley et al., 2013;
Kishi et al., 2016; Lian et al., 2022a). ‘EP’ is used in the next sections as a
generic term including all these definitions.

In most reviews (N = 7), all LAIs were considered, including both
first-generation (FGA) and second-generation antipsychotics (SGA)
(Emsley et al., 2013; Kirschner et al., 2013; Lian et al., 2022a, 2022b;
Taylor and Ng, 2013; Vita et al., 2024; Zhornitsky and Stip, 2012). Two
reviews included only studies about SGA LAIs in EP (Correll et al.,
2022b; Salgueiro and Segarra, 2019). One meta-analysis considered all
LAIs, although only articles about SGA LAIs were finally included (Kishi
et al., 2016). One systematic review focused on risperidone-LAIs
(Parellada, 2007).

Various comparators against LAIs were used: OAPs (Emsley et al.,

2013; Kishi et al., 2016; Lian et al., 2022a, 2022b; Salgueiro and
Segarra, 2019; Taylor and Ng, 2013; Vita et al., 2024; Zhornitsky and
Stip, 2012), periods without LAIs (Emsley et al., 2013; Lian et al., 2022a;
Parellada, 2007; Salgueiro and Segarra, 2019; Taylor and Ng, 2013),
placebo (Emsley et al., 2013; Lian et al., 2022a; Taylor and Ng, 2013), or
no antipsychotic use (Correll et al., 2022b). EP patients were compared
to patients with a longer duration of illness in two reviews (Emsley et al.,
2013; Lian et al., 2022a).

Ten reviews (Correll et al., 2022b; Emsley et al., 2013; Kishi et al., 2016; Lian et al., 2022a, 2022b; Parellada, 2007; Salgueiro and Segarra, 2019; Taylor and Ng, 2013; Vita et al., 2024; Zhornitsky and Stip, 2012) assessed the efficacy or effectiveness of LAIs on symptomatic outcome (N = 7), medication adherence and/or treatment discontinuation (N = 8), relapse (N = 8), remission (N = 4), and mortality (N = 2). ADR were evaluated by six reviews (Emsley et al., 2013; Kishi et al., 2016; Lian et al., 2022a; Parellada, 2007; Taylor and Ng, 2013; Vita et al., 2024). One systematic review assessed patients' and clinicians' opinion about
<table><caption>**Table 1**

Characteristics of included systematic reviews and meta-analyses.</caption><thead><tr><th>Reference and study type</th><th>Objective(s)</th><th>Database Date of research Search algorithm</th><th>Studies</th><th>Population</th><th>Intervention</th><th>Mean follow-up duration (months)</th><th>Outcome(s)</th></tr></thead><tbody><tr><td>Parellada, 2007 Systematic review</td><td>Efficacy and safety of risperidone-LAI<sup>1</sup> in patients groups, including young adults with first-episode SZ<sup>2</sup></td><td>Embase, MEDLINE 01/2002–11/2005 Search algorithm: NS<sup>3</sup>, keyword “long acting risperidone”</td><td>N<sup>4</sup> = 10, including 4 articles about first-episode SZ Study design: open-label studies (N = 2), subanalyses from open-label studies (N = 2) Publication date: from 2004 to 2007 PubMed, Embase 01/1960–07/2011</td><td>n<sup>5</sup> (first-episode SZ patients) = 610 Target population: young adults with first-episode SZ</td><td>Medication: risperidone-LAI (N = 4) Comparator: period without LAIs AP<sup>6</sup> (N = 4)</td><td>6.875 (12–50 weeks)</td><td>- Symptomatic outcome (PANSS<sup>7</sup>, CGI–S<sup>8</sup>) (N = 4) - ADR<sup>9</sup>: extrapyramidal symptoms (N = 4)</td></tr><tr><td>Zhornitsky and Stip, 2012 Systematic review</td><td>Efficacy and tolerability of LAIs vs. oral forms of the same AP in SZ patients, including FEP<sup>10</sup></td><td>Search algorithm: “antipsychotic” AND “depot” OR “injectable” AND “randomized” OR “naturalistic” OR “first-episode” OR “noncompliance” OR “substance abuse” OR “substance use disorder” OR “alcohol” OR “drug” OR “cannabis” OR “cocaine” OR “heroin” OR “amphetamine” OR “violence” OR “involuntary outpatient commitment” OR “community treatment order”</td><td>N = 18, including 3 articles about FEP patients Study design: naturalistic designs, including prospective cohort studies (N = 2), randomized open-label trial (N = 1) Publication date: from 2006 to 2011 MEDLINE, Web of Knowledge, grey literature (Conference Proceedings) 1982–2011</td><td>n = 4868 (FEP patients) Target population: patients with FEP, at risk for treatment nonadherence</td><td>Medication: all LAIs considered, except PP<sup>11</sup> perphenazine-LAI (N = 1), risperidone-LAI (N = 1), FGA<sup>12</sup> and SGA LAIs<sup>13</sup> (N = 1) Comparator: OAPs (N = 3)</td><td>30.4 (24 months–3.6 years)</td><td>- Discontinuation / adherence (N = 3) - Relapse (N = 3)</td></tr><tr><td>Emsley et al., 2013 Systematic review</td><td>Use of LAIs in FEP and early SZ</td><td>Search algorithm: NS, keywords “long-acting antipsychotic”, “long acting injection”, “depot”, “schizophrenia”, “early psychosis”, “recent onset”, “first-episode”</td><td>N = 17 Study design: RCTs<sup>14</sup> (N = 3), post-hoc analyses (N = 7), non-comparative studies (N = 4), cohort studies (N = 2) Publication date: from 1982 to 2011 MEDLINE, Embase, PsycINFO, Google Scholar</td><td>n = 6807 Target population: FEP or early psychosis</td><td>Medication: all LAIs considered FGA-LAIs (N = 3), risperidone-LAI (N = 9), olanzapine-LAI (N = 1), PP (N = 2), FGA and SGA LAIs (N = 2) Comparator: placebo (N = 3), OAPs<sup>15</sup> (N = 5), period without LAIs AP (N = 7), duration of illness >3 years (N = 1), duration of illness >5 years (N = 1)</td><td>22.5 (12 weeks–7 years)</td><td>- Symptomatic outcome (N = 8) - Discontinuation / adherence (N = 9) - Relapse (N = 9) - Remission (N = 6) - ADR: extrapyramidal symptoms (N = 8), metabolic adverse effects (N = 5; weight gain (N = 5); dyslipidemia and/or glucose-related ADR (N = 4)), hyperprolactinemia (N = 4)</td></tr><tr><td>Kirschner et al., 2013 Systematic review</td><td>Attitudes and preferences of patients and mental health professionals towards the use of LAIs in FEP</td><td>Inception-11/2011 Search algorithm: NS, keywords “antipsychotic LAI”, “depot”, “delayed action preparations”, “intramuscular</td><td>N = 6 Study design: cross-sectional survey (N = 6) Publication date: from 2003 to 2011</td><td>n = 1145 Target population: patients' and/or clinicians' attitudes (i. e. any opinion) towards LAIs in the treatment of FEP</td><td>Medication: all LAIs considered Comparator: NS</td><td>NS</td><td>- Clinicians' attitudes (N = 6)</td></tr></tbody></table>

(continued on next page)
<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Reference and study type</th><th>Objective(s)</th><th>Database Date of research Search algorithm</th><th>Studies</th><th>Population</th><th>Intervention</th><th>Mean follow-up duration (months)</th><th>Outcome(s)</th></tr></thead><tbody><tr><td>Taylor and Ng, 2013<br>Systematic review</td><td>Safety and efficacy of LAIs in early SZ</td><td>injection" combined with "first-episode psychosis", "schizophrenia", "attitude", "satisfaction" and related terms<br>Embase, MEDLINE, Cochrane, PsycINFO<br>1982–2011<br>Search algorithm: (long-acting injection OR depot OR long-acting antipsychotic) AND (psychosis OR schizophrenia OR schizoaffective) AND (first episode OR early OR acute)<br>MEDLINE, Cochrane, PsycINFO<br>WHO International Clinical Trials Registry Platform<br>ClinicalTrials.gov</td><td>N = 10 studies<br>Study design: RCTs (N = 3), cohort studies (N = 2), open-label studies (N = 5)<br>Publication date: from 1982 to 2011<br>N = 5 studies<br>Inception-07/05/2016</td><td>n = 5762 patients<br>Target population: FEP or early stages with a diagnosis of SZ, psychosis or SZA<br>n = 1022 patients<br>Study design: 5 RCTs, with ITT<sup>17</sup> or modified ITT analyses<br>Publication date: from 2009 to 2015<br>N = 5</td><td>Medication: all LAIs considered FGA-LAIs (N = 1), risperidone-LAI (N = 7), FGA and SGA LAIs (N = 2)<br>Comparator: placebo (N = 1), OAPs (N = 5), period without LAIs AP (N = 4)<br>Medication: all LAIs considered risperidone-LAI (N = 4), PP (N = 1)<br>Comparator: OAPs (N = 5)<br>Medication: only SGA-LAIs considered, risperidone-LAI (N = 5)<br>Comparator: OAPs (N = 4), period without LAIs AP (N = 1)</td><td>26 (12 weeks-7 years)<br>18 (6–24 months)<br>17.4 (12 weeks-24 months)<br>NS</td><td>- Symptomatic outcome (PANSS, CGI–S, GAF<sup>16</sup>) (N = 5)<br>- Discontinuation/ adherence (N = 7)<br>- Relapse (N = 5)<br>- Remission (N = 3)<br>- ADR: extrapyramidal symptoms (N = 5), metabolic adverse effects (N = 3); weight gain (N = 3), dyslipidemia and/or glucose-related ADR (N = 2), hyperprolactinemia (N = 3)<br>- Symptomatic outcome (PANSS) (N = 2)<br>- Discontinuation due to inefficacy (N = 3)<br>- Discontinuation due to nonadherence (N = 2)<br>- Discontinuation rates: all-cause (N = 4), death (N = 3), ADR (N = 3)<br>- Relapse (N = 3)<br>- ADR: extrapyramidal symptoms (N = 3), metabolic adverse effects (weight gain (N = 3)), hyperprolactinemia (N = 2)<br>- Symptomatic outcome (PANSS, CGI–S, BPRS) (N = 3)<br>- Adherence (N = 4)<br>- Relapse (N = 2)<br>- Remission (N = 1)</td></tr><tr><td>Kishi et al., 2016<br>Systematic review and meta-analysis</td><td>Efficacy, discontinuation rates, and ADR of LAIs compared to OAPs in recent-onset psychotic disorders</td><td>Search algorithm: "schizophrenia AND randomized AND recent diagnosed or first episode or early phase AND depot, enanthate, decanoate, long-acting injection, microsphere, once monthly, palmitate or pamoate"<br>PubMed, Scopus<br>01/01/2000–04/30/2018</td><td>N = 5<br>Study design: 5 RCTs, with ITT<sup>17</sup> or modified ITT analyses<br>Publication date: from 2008 to 2015<br>N = 135, including 1 study about LAIs use in incident SZ</td><td>n = 220<br>Target population: FEP<br>Study design: prospective cohort studies (N = 22), retrospective cohort studies (N = 113)<br>n (total) = 4,536,447 individuals with SZ, 1115600059 control subjects.<br>n = 719 (incident SZ cohort receiving SGA LAIs)<br>Target population: SZ, including incident SZ, with a quantitative measure of the</td><td>Medication: SGA LAIs (N = 1)<br>Comparator: no AP use (N = 1)</td><td>NS</td><td>- Mortality (incident SZ, LAIs treatment): all-cause (N = 1)</td></tr><tr><td>Salgueiro and Segarra, 2019<br>Systematic review</td><td>Long-term effects of SGA-LAIs in patients with FEP on adherence, relapse and remission</td><td>Search algorithm: (psychosis OR schizophrenia) AND ("first episode" OR "first-episode" OR "new-onset" OR "early intervention") AND (LAI OR "long-acting injectable" OR "long acting injectable" OR injectable OR injection OR depot)<br>MEDLINE, PubMed, PsycINFO</td><td>N = 135, including 1 study about LAIs use in incident SZ<br>Study design: prospective cohort studies (N = 22), retrospective cohort studies (N = 113)</td><td>n (total) = 4,536,447 individuals with SZ, 1115600059 control subjects.<br>n = 719 (incident SZ cohort receiving SGA LAIs)<br>Target population: SZ, including incident SZ, with a quantitative measure of the</td><td>Medication: SGA LAIs (N = 1)<br>Comparator: no AP use (N = 1)</td><td>NS</td><td>- Mortality (incident SZ, LAIs treatment): all-cause (N = 1)</td></tr><tr><td>Correll et al., 2022<br>Systematic review and meta-analysis</td><td>Risk of all-cause and specific-cause mortality in individuals with SZ, including incident SZ</td><td>Inception- 09/09/2021<br>Search algorithm: (schizophrenia AND (mortal* OR death* or fatal*) NOT (animals NOT humans))</td><td>N = 135, including 1 study about LAIs use in incident SZ<br>Study design: prospective cohort studies (N = 22), retrospective cohort studies (N = 113)</td><td>n (total) = 4,536,447 individuals with SZ, 1115600059 control subjects.<br>n = 719 (incident SZ cohort receiving SGA LAIs)<br>Target population: SZ, including incident SZ, with a quantitative measure of the</td><td>Medication: SGA LAIs (N = 1)<br>Comparator: no AP use (N = 1)</td><td>NS</td><td>- Mortality (incident SZ, LAIs treatment): all-cause (N = 1)</td></tr></tbody></table>

(continued on next page)
<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Reference and study type</th><th>Objective(s)</th><th>Database Date of research Search algorithm</th><th>Studies</th><th>Population</th><th>Intervention</th><th>Mean follow-up duration (months)</th><th>Outcome(s)</th></tr></thead><tbody><tr><td>Lian et al., 2022a<br>Systematic review</td><td>Efficacy of FGA and SGA-LAIs in recent-onset, first-episode and early psychosis patients</td><td>MEDLINE, Embase, PsycINFO, Web of Science Core<br>Inception-06/06/2019<br>Search algorithm: (“neuroleptic agent MESH” OR “antipsychotic” OR “anti-psychotic”) AND (“depot” OR “long-acting” OR “long acting”) AND (“first-episode psychosis” OR “first episode psychosis” OR “early psychosis” OR “early psychotic” OR “first psychotic episode” OR “recent-onset” OR “recent onset”) Embase, MEDLINE, PsycINFO, Web of Science Core</td><td>N = 33<br>Study design: RCTs (N = 8), naturalistic studies (N = 19), post-hoc analyses (N = 4), case reports (N = 2)<br>Publication date: from 1977 to 2020</td><td>relationship between SZ and mortality vs any control group<br>n = 14,313<br>Target population: diagnosis of SZ or related disorder, first-episode, recent-onset, early psychosis, or duration of illness ≤5 years if no specified definition</td><td>Medication: all LAIs considered risperidone-LAI (N = 14), PP (N = 10), FGA-LAIs (N = 5), aripiprazole-LAI (N = 1), several LAIs (N = 1), NS (N = 2)<br>Comparator: placebo (N = 1), OAPs (N = 14), OAPs and placebo (N = 1), period without LAIs AP (N = 12), longer duration of illness (N = 4), non-adherent patients (N = 1)</td><td>21.9 (3 months-20 years)</td><td>- Symptomatic outcome (N = 18)<br>- Adherence (N = 9)<br>- Discontinuation (N = 15)<br>- Relapse (N = 12)<br>- Remission (N = 8)<br>- ADR: extrapyramidal symptoms (N = 15), metabolic adverse effects (N = 10; weight gain (N = 10), dyslipidemia and/or glucose-related ADR (N = 3)), hyperprolactinemia (N = 7), discontinuation due to ADR (N = 3)</td></tr><tr><td>Lian et al., 2022b<br>Systematic review and meta-analysis</td><td>Efficacy of LAIs versus OAPs in the early stages of psychosis in terms of adherence, relapse, rehospitalization, discontinuation rates</td><td>Inception-06/06/2019<br>Search algorithm: (“neuroleptic agent” OR “antipsychotic” OR “anti-psychotic”) AND (“depot” OR “long-acting” OR “long acting”) AND (“first-episode psychosis” OR “first episode psychosis” OR “early psychosis” OR “early psychotic” OR “first psychotic episode” OR “recent-onset” OR “recent onset”) MEDLINE, Embase, PsycINFO, CENTRAL, Cochrane Central Register of Controlled Trials + additional hand search on websites of regulatory agencies, pharmaceutical companies producing antipsychotics, clinical trials repositories</td><td>N = 15<br>Study design: RCTs (N = 7), post-hoc analysis (N = 1), observational studies (N = 7)<br>Publication date: from 1977 to 2019</td><td>n = 10,584<br>Target population: first-episode, recent-onset, early psychosis patients with a mean duration of illness ≤5 years.</td><td>Medication: all LAIs considered risperidone-LAI (N = 8), PP (N = 3), FGA and SGA LAIs (N = 2), FGA LAIs (N = 1), NS (N = 1)<br>Comparator: OAPs (N = 14), OAPs and placebo (N = 1)</td><td>32.5 (6 months-20 years)</td><td>- Discontinuation rates: all-cause (N = 9), due to adverse events (N = 5), due to non-adherence (N = 2), due to inefficacy (N = 4)<br>- Adherence (N = 7)<br>- Relapse (N = 7)</td></tr><tr><td>Vita et al., 2024<br>Systematic review and meta-analysis</td><td>Efficacy, effectiveness and safety of LAIs versus OAPs for maintenance treatment of patients with early phase SSDs<sup>18</sup></td><td>Inception-01/24/2023<br>Search algorithm: (schizophreni* OR schizoaffective OR psychosis OR psychotic) AND (“first episode” OR first-episode OR first psychotic OR FEP OR “early phase” OR early-phase OR “recent onset” OR recent-onset</td><td>N = 11<br>Study design: RCTs (N = 11), including patient-level randomized (N = 10) and cluster-randomized RCTs (N = 1)<br>Publication date: from 1977 to 2023</td><td>n = 2374<br>Target population: acutely ill and stable patients with a FEP or a study-defined recent diagnosis of SZ or SSDs (SZ, SZA<sup>19</sup>, schizophreniform disorder, brief psychotic episode and delusional disorder), with a mean recency of onset of disease ≤5 years</td><td>Medication: all LAIs considered risperidone-LAI (N = 4), PP (N = 4), FGA-LAIs (N = 1), aripiprazole-LAI (N = 1), aripiprazole-LAI and PP (N = 1)<br>Comparator: OAPs (N = 10), clinician's choice (N = 1)</td><td>78 weeks (13–104 weeks)</td><td>- Symptomatic outcome (PANSS (N = 7), CGI-S (N = 5), GAF (N = 5))<br>- All-cause discontinuation (N = 11)<br>- Discontinuation due to inefficacy (N = 8), due to adverse events (N = 9)<br>- Relapse or hospitalization when relapse not reported (N = 10)<br>- ADR: extrapyramidal symptoms (N = 7), akathisia (N = 8), metabolic adverse effects (weight gain: BMI<sup>20</sup> change (N = 4), weight increase (N = 10)), hyperprolactinemia (N = 10)</td></tr></tbody></table>

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<table><caption>**Table 1 (continued)**</caption><thead><tr><th>Reference and study type</th><th>Objective(s)</th><th>Database Date of research Search algorithm</th><th>Studies</th><th>Population</th><th>Intervention</th><th>Mean follow-up duration (months)</th><th>Outcome(s)</th></tr></thead><tbody><tr><td></td><td></td><td>OR newly) AND (“long acting” OR long-acting OR LAI OR depot OR injectable OR injection) AND (antipsychotic* OR neuroleptic* OR “dopamine antagonist” OR “dopamine blocker” OR “dopamine partial agonist”) AND (random* OR head-to-head OR RCT OR placebo)</td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

1. LAIs = long-acting injectable antipsychotic; 2. SZ = schizophrenia; 3. NS = not specified; 4. N = number of studies; 5. n = number of patients; 6. AP = antipsychotic; 7. PANSS = positive and negative syndrome scale; 8. CGI-S = clinical global impression – severity; 9. ADR = adverse drug reactions; 10. FEP = first-episode of psychosis; 11. PP = paliperidone palmitate; 12. FGA LAI = long acting injectable formulation of first generation antipsychotics; 13. SGA LAI = long acting injectable formulation of second generation antipsychotics; 14. RCT = randomized controlled trial; 15. OAPs = oral antipsychotic; 16. GAF = Global Assessment of Functioning; 17. ITT = intention to treat; 18. SSDs = schizophrenia spectrum disorders; 19. SZA = schizoaffective disorder; 20. BMI = body mass index.

LAIs use in EP (Kirschner et al., 2013).

## 3.2. Quality assessment of included meta-analyses and systematic reviews

All reviews presented a comprehensive literature search strategy and described the individual studies included in adequate detail (supplementary Table 1). 10 out of 11 reviews reported any potential source of conflict of interest. The four meta-analyses used a structured method to assess the risk of bias in individual studies, whereas none of the systematic reviews fulfilled this criterion. Only one review had previously registered the review protocol. Overall, eight out of 11 reviews presented at least one critical weakness: one of them presented a moderate quality of evidence, while two recent systematic reviews and meta-analyses presented a high quality of evidence. The corrected covered area value was equal to 8.97 % (supplementary Table 2) corresponding to “moderate” publication overlap (Pieper et al., 2014).

## 3.3. Efficacy/effectiveness of LAIs in EP

### 3.3.1. Symptomatic outcome

Five systematic reviews concluded that LAIs had a positive impact on symptoms in EP (Emsley et al., 2013; Lian et al., 2022a; Parellada, 2007; Salgueiro and Segarra, 2019; Taylor and Ng, 2013). They reported a significant reduction in Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression–Severity (CGI–S) or Global Assessment of Functioning (GAF) scores after LAIs introduction compared to periods without LAIs treatment (Emsley et al., 2013; Lian et al., 2022a; Parellada, 2007; Salgueiro and Segarra, 2019; Taylor and Ng, 2013), or compared to OAPs (Emsley et al., 2013; Lian et al., 2022a; Salgueiro and Segarra, 2019; Taylor and Ng, 2013), with a total PANSS score reduction >20 % in up to 84 % of EP patients. One review suggested that the effects of LAIs on symptoms may be greater in EP patients than in those with a longer duration of illness, although this outcome was assessed by only three studies (Lian et al., 2022a).

In contrast, two meta-analyses found a similar efficacy between LAIs and OAPs regarding symptomatic outcome in EP (Kishi et al., 2016; Vita et al., 2024). The first one found no significant differences between LAIs and OAPs in terms of decrease in total PANSS score (weighted mean differences –2.26; 95%CI -5.22 to 0.70; *p* = 0.13) (Kishi et al., 2016). A recent meta-analysis also found no significant differences between LAIs and OAPs in total (standardized mean difference (SMD) -0.04; 95%CI -0.12 to 0.04), positive (SMD -0.06; 95%CI -0.16 to 0.04) and negative

PANSS scores (SMD 0.02; 95%CI -0.20 to 0.23), in CGI–S scores (SMD -0.12; 95%CI -0.32 to 0.08) and in GAF scores (SMD 0.16; 95%CI -0.06 to 0.39) (Vita et al., 2024).

### 3.3.2. Treatment discontinuation

The selected reviews used the measures of adherence chosen by each individual studies when specified: adherence was broadly defined as the extent to which a patient's behavior, including taking medications, was in line with medical advice (Taylor and Ng, 2013). Nonadherence was defined as a medication gap of at least 14 consecutive days with complete discontinuation of all antipsychotic medication (Emsley et al., 2013; Lian et al., 2022a; Salgueiro and Segarra, 2019). Adherence was defined as the proportion of days with medication across the study period or as the number of actual visits to the outpatient clinic divided by the number of scheduled visits (Lian et al., 2022a). Other studies used self-report rating scales such as the Rating of Medication Influences (ROMI) scale (Emsley et al., 2013), or clinician-rated scales such as a 1–5 Likert scale based on timeliness of injections or pill counts, patient reports, plasma levels of risperidone and 9-hydroxyrisperidone and psychiatrist judgments for OAPs (Lian et al., 2022a).

Five systematic reviews reported a positive effect of LAIs compared to the period before their introduction or to OAPs on adherence (N = 5) (Emsley et al., 2013; Lian et al., 2022a; Salgueiro and Segarra, 2019; Taylor and Ng, 2013; Zhornitsky and Stip, 2012) and/or all-cause treatment discontinuation rates (N = 4) (Emsley et al., 2013; Lian et al., 2022a; Taylor and Ng, 2013; Zhornitsky and Stip, 2012). Adherence rates ranged from 21 % (over 24 months) to 95 % (over 12 months) and discontinuation rates from 16 % (over 12 months) to 49 % (over 24 months).

Three meta-analyses found no significant differences between LAIs and OAPs in terms of (i) all-cause discontinuation risk [relative risks (RR) of 0.90 (95%CI 0.75 to 1.08; *p* = 0.25) (Kishi et al., 2016), 0.89 (95%CI 0.72 to 1.09; *p* = 0.27) (Lian et al., 2022b) and 0.92 (95%CI 0.80 to 1.05; *p* = 0.20) (Vita et al., 2024)]; and (ii) discontinuation due to ADR [RR of 1.15 (95%CI 0.36 to 3.68; *p* = 0.81) (Kishi et al., 2016), 1.59 (95%CI 0.62 to 4.07; *p* = 0.33) (Lian et al., 2022b) and 1.01 (95%CI 0.76 to 1.34) (Vita et al., 2024)]. In one meta-analysis, all-cause discontinuation rates were reduced with LAIs compared to OAPs in a subgroup analysis on studies including only patients with strictly defined schizophrenia (RR 0.87; 95%CI 0.79–0.95; *p* < 0.01) whereas no significant difference was found in studies including patients with schizophrenia spectrum disorders (RR 1.08; 95%CI 0.87–1.48; *p* = 0.65) (Vita et al.,
2024). Four other subgroup analyses found reduced all-cause discontinuation rates with LAIs vs. OAPs (clinically unstable patients, illness duration <2 years, OAPs supplementation allowed in LAIs group, no long OAPs run-in phase) (Vita et al., 2024). Meta-regression analysis performed by one meta-analysis found that follow-up duration (median 78 weeks, IQR = 52–104, range = 13–104) did not moderate the association between type of treatment (LAIs vs. OAPs) and risk of all-cause treatment discontinuation (p = 0.925) (Vita et al., 2024).

Two meta-analyses found that LAIs outperformed OAPs in terms of discontinuation due to inefficacy [RR of 0.34 (95%CI 0.12 to 0.92; p = 0.03) (Kishi et al., 2016) and 0.35 (95%CI 0.13 to 0.96; p = 0.04) (Lian et al., 2022b)]. These results were not confirmed by a third meta-analysis (RR 0.73; 95%CI 0.40 to 1.33) (Vita et al., 2024).

LAIs were found superior to OAPs regarding discontinuation due to nonadherence in two meta-analyses [0.30 (95%CI 0.11 to 0.82; p = 0.02) (Kishi et al., 2016) and 0.31 (95%CI 0.11 to 0.87; p = 0.03) (Lian et al., 2022b)].

### 3.3.3. Relapse

Five systematic reviews (Emsley et al., 2013; Lian et al., 2022a; Salgueiro and Segarra, 2019; Taylor and Ng, 2013; Zhornitsky and Stip, 2012) and three meta-analyses (Kishi et al., 2016; Lian et al., 2022b; Vita et al., 2024) assessed relapse rates and time to relapse. Relapse was defined in most of studies using Csernansky criteria (Csernansky et al., 2002) or by clinically significant changes in rating scales scores (PANSS, Brief Psychiatric Rating Scale (BPRS), or CGI–S), or in level of psychiatric care (psychiatric hospitalization rates, frequency of outpatient visits, psychiatric emergency visits, adjustment in medication needed, requirement for more than a study-defined period of oral therapy).

Five systematic reviews found lower overall relapse rates for EP patients receiving LAIs compared to those receiving OAPs (Emsley et al., 2013; Lian et al., 2022a; Salgueiro and Segarra, 2019; Taylor and Ng, 2013; Zhornitsky and Stip, 2012) or to those with chronic disorders (Emsley et al., 2013; Lian et al., 2022a; Taylor and Ng, 2013), with overall relapse rates ranging between 8 % and 26 % over 24 months. Additionally, these reviews noted a reduced risk of hospitalization with LAIs compared to OAPs (Emsley et al., 2013; Lian et al., 2022a; Salgueiro and Segarra, 2019; Taylor and Ng, 2013; Zhornitsky and Stip, 2012), with hospitalization rates ranging from 2.4 % (over 15 months) to 58 % (over 24 months). One meta-analysis also found lower relapse rates with LAIs compared to OAPs in EP (RR 0.58; 95%CI 0.34 to 1.01; p = 0.05) (Lian et al., 2022b).

Two meta-analyses found no significant differences between LAIs and OAPs in terms of relapse prevention (Kishi et al., 2016; Vita et al., 2024). LAIs did not significantly outperform OAPs in reducing the risk of relapse (RR 0.67; 95%CI 0.24 to 1.83; p = 0.43), although there was significant heterogeneity between the studies (Kishi et al., 2016). No significant difference was found between LAIs and OAPs in terms of risk of hospitalizations (RR 0.81; 95%CI 0.57 to 1.15) or relapse irrespective of the definition (RR 0.79; 95%CI 0.58 to 1.06; p = 0.13) (Vita et al., 2024). A subgroup analysis found no advantage of LAIs over OAPs regarding relapse prevention whether patients presented with strictly defined schizophrenia (RR 0.79; 95%CI 0.55–1.13; p = 0.20) or with schizophrenia spectrum disorders (RR 0.73; 95%CI 0.38–1.40; p = 0.35) (Vita et al., 2024). In a meta-regression analysis from one meta-analysis, follow-up duration did not moderate the association between type of treatment (LAIs vs. OAPs) and risk of relapse or hospitalization (p = 0.370) (Vita et al., 2024). Nevertheless, four subgroup analyses showed that LAIs significantly reduced relapse risk in clinically stable patients, real-world pragmatic studies, strict intention-to-treat analyses, and studies selecting the oral treatment in the OAPs group on the basis of prior treatment response history (Vita et al., 2024). Another meta-analysis focusing on the risk of hospitalization found no significant difference between LAIs and OAPs (OR 0.57; 95%CI 0.30 to 1.08; p = 0.08) (Lian et al., 2022b). When only RCTs were considered, the risk of hospitalization was lower for LAIs compared to OAPs (OR 0.38; 95%CI

0.14 to 1.0; p = 0.05) (Lian et al., 2022b).

### 3.3.4. Remission

Definitions of remission used in the reviews were those chosen in each individual study, e.g. Schizophrenia Working Group criteria (Emsley et al., 2013; Salgueiro and Segarra, 2019; Taylor and Ng, 2013), Andreasen criteria (Andreasen et al., 2005) or PANSS scores (Emsley et al., 2013; Lian et al., 2022a; Taylor and Ng, 2013).

Four systematic reviews assessed this issue with remission rates in EP patients using LAIs ranging from 20.2 % to 64 % over 24 months (Emsley et al., 2013; Lian et al., 2022a; Salgueiro and Segarra, 2019; Taylor and Ng, 2013). They suggested that LAIs may be associated with higher remission rates compared to OAPs or in EP patients compared to those with chronic disorders (Emsley et al., 2013; Lian et al., 2022a; Taylor and Ng, 2013). Since this point was assessed by a limited number of studies in each review (one to eight), none of them reached a formal conclusion about this outcome.

### 3.3.5. Mortality

Two meta-analyses based on a limited number of studies (one to three) assessed mortality (Correll et al., 2022b; Kishi et al., 2016). No significant difference was found between LAIs and OAPs regarding treatment discontinuation due to patient's death (RR 1.03; 95%CI 0.06 to 16.42; p = 0.98) (Kishi et al., 2016). SGA LAIs significantly reduced all-cause mortality compared to no antipsychotic use (RR 0.15; 95%CI 0.04 to 0.55), whereas no protective effect was found for OAPs or FGA LAIs (Correll et al., 2022b).

## 3.4. Adverse drug reactions

### 3.4.1. Extrapyramidal symptoms

Four systematic reviews (Emsley et al., 2013; Lian et al., 2022a; Parellada, 2007; Taylor and Ng, 2013) and two meta-analyses (Kishi et al., 2016; Vita et al., 2024) assessed extrapyramidal symptoms (EPS). EPS were most often assessed by using rating scales ((Extrapyramidal Symptom Rating Scale (ESRS), Barnes Akathisia Scale (BAS), Abnormal Involuntary Movement Scale (AIMS)), while some included studies used non-standardized physician rating of EPS.

Four systematic reviews reported no significant differences or significantly reduced ESRS scores with LAIs compared to OAPs, with EPS rates ranging from 3.2 % to 20 % (Emsley et al., 2013; Lian et al., 2022a; Parellada, 2007; Taylor and Ng, 2013). Two meta-analyses both found no significant differences between LAIs or OAPs regarding the following: incidence of all EPS (RR 1.29; 95%CI 0.77 to 2.17) (Vita et al., 2024), akathisia (RR 1.50; 95%CI 0.84 to 2.67) (Vita et al., 2024) (RR 0.96; 95%CI 0.51 to 1.83; p = 0.91) (Kishi et al., 2016), restlessness (RR 1.65; 95% CI 0.40 to 6.70; p = 0.49) (Kishi et al., 2016), abnormal movement disorders (RR 0.59; 95% CI 0.09 to 3.91; p = 0.59) (Kishi et al., 2016), BAS scores (weighted mean differences -0.03; 95% CI -0.32 to 0.26; p = 0.84) and AIMS scores (weighted mean differences -0.05; 95% CI -0.16 to 0.06; p = 0.41) (Kishi et al., 2016). However, in one meta-analysis, LAIs were associated with a significantly higher incidence of tremor compared to OAPs (RR 2.38; 95% CI 1.10 to 5.13; p = 0.03) (Kishi et al., 2016).

### 3.4.2. Metabolic ADR

Three systematic reviews reported that LAIs use in EP was associated with a risk of weight gain (up to 2.6 kg over 12 months) or Body Mass Index (BMI) increase (up to 4.8 kg/m² over 24 months) (Emsley et al., 2013; Lian et al., 2022a; Taylor and Ng, 2013). This risk was not significantly different with LAIs vs. OAPs use (Emsley et al., 2013; Lian et al., 2022a; Taylor and Ng, 2013) or in EP patients vs. patients with chronic disorders (Emsley et al., 2013; Lian et al., 2022a). Two meta-analyses found no significant differences between LAIs and OAPs in EP regarding weight gain [(RR = 0.96 (95%CI 0.71 to 1.30; p = 0.79) (Kishi et al., 2016) and 1.03 (95%CI 0.87 to 1.23) (Vita et al., 2024)] or BMI
changes [(SMD = 0.07 (95%CI -0.06 to 0.20; *p* = 0.28) (Kishi et al., 2016) and 0.00 (95% CI -0.24 to 0.24) (Vita et al., 2024)].

Three systematic reviews assessed dyslipidemia and glucose-related ADR, based on a limited number of studies (two to four studies included) (Emsley et al., 2013; Lian et al., 2022a; Taylor and Ng, 2013). Increased blood cholesterol with LAIs was reported in two systematic reviews (Emsley et al., 2013; Taylor and Ng, 2013), although cholesterol levels were similar with LAIs vs. OAPs (Lian et al., 2022a) and in EP patients vs. patients with chronic disorders (Emsley et al., 2013). Levels of glucose did not differ significantly in EP patients vs. patients with chronic disorders (Emsley et al., 2013).

### 3.4.3. Hyperprolactinemia

Three systematic reviews reported that up to 8% of EP patients using LAIs presented with prolactin-related ADR such as galactorrhea, gonecomastia or amenorrhea (Emsley et al., 2013; Lian et al., 2022a; Taylor and Ng, 2013). One systematic review concluded that prolactin levels and prolactin-related ADR did not differ with LAIs vs. OAPs (Lian et al., 2022a). Two meta-analyses confirmed that there were no significant differences between LAIs and OAPs concerning prolactin increase (RR 1.11; 95%CI 0.68 to 1.81) (Vita et al., 2024) and prolactin-related ADR such as amenorrhea (RR 2.22; 95%CI 0.94 to 5.25; *p* = 0.07), galactorrhea (RR 3.97; 95%CI 0.86 to 18.33; *p* = 0.08), and erectile dysfunction (RR 1.66; 95%CI 0.40 to 6.86; *p* = 0.49) (Kishi et al., 2016).

## 3.5. Users' or clinicians' attitude towards LAIS prescription

One systematic review identified six surveys on clinicians' attitude towards LAIs prescription in EP, but no study addressed the attitude of EP patients about LAIs (Kirschner et al., 2013). Most surveys reported negative attitudes of psychiatrists towards LAIs, which were considered as not appropriate or recommended only in the early stages of schizophrenia, and so rarely proposed to patients. Two studies reported that for >60% of UK psychiatrists, LAIs were appropriate for EP patients aged under 30 years.

## 3.6. Impact of industrial funding

Only one of the four meta-analyses performed sensitivity analyses to assess the impact of pharmaceutical funding or sponsorship on the results (Vita et al., 2024). No significant difference was found between LAIs and OAPs regarding risk of relapse and acceptability in EP, regardless of whether the individual studies were industry-sponsored or not (Vita et al., 2024). Conflicts of interest were reported in most reviews (Correll et al., 2022b; Emsley et al., 2013; Kishi et al., 2016; Lian et al., 2022a, 2022b; Taylor and Ng, 2013; Vita et al., 2024; Zhornitsky and Stip, 2012), and some of them benefited from direct funding or subsidies from industry sources (Correll et al., 2022b; Lian et al., 2022a; Parellada, 2007).

# 4. Discussion

## 4.1. Main findings

This umbrella review included seven systematic reviews and four meta-analyses on LAIs in EP published from 2007 to 2024 including 58 unique primary studies. Their findings indicate that LAIs has a positive impact on symptomatic outcome, although there is no clear consensus on whether LAIs consistently outperform OAPs. LAIs may be associated with a greater reduction of treatment discontinuation due to inefficacy or nonadherence compared to OAPs, with similar efficacy in terms of all-cause discontinuation. Findings regarding relapse prevention were inconclusive, as meta-analyses reported either comparable efficacy of LAIs and OAPs, a trend in favor of LAIs, or LAIs outperforming OAPs only in specific subgroups of patients. The umbrella review also found that LAIs use in EP is associated with similar rates of metabolic ADR and

potentially lower rates of EPS compared to OAPs.

## 4.2. Limitations

The present findings should be considered in the light of potential limitations. First, the individual studies included in the reviews were hampered by methodological limitations. Most of them were observational or non-comparative studies, or RCTs involving small samples resulting in low statistical power. The follow-up time was frequently <12 months. There was a great heterogeneity in definitions and measurement criteria for major outcomes, such as relapse and remission. A reliable assessment method of adherence (blood level) was used in only one study. The populations were also heterogeneous regarding duration of illness, ranging from EP to up to five years after illness onset. Consequently, most of the included reviews presented a low or critically low quality of evidence. In spite of these limitations, convergent findings are provided by these reviews regarding the positive impact of LAIs on symptom outcome and discontinuation due to nonadherence, with similar ADR rates compared to OAPs.

Second, there were limitations in the systematic reviews and meta-analyses themselves. Of the 11 reviews, only one mentioned that its protocol was previously registered, and only five detailed their inclusion criteria for study designs. The four meta-analyses conducted a satisfactory assessment of the risk of bias in individual studies, whereas none of the narrative systematic reviews performed this evaluation. However, two recent meta-analyses provided useful high-quality results (Correll et al., 2022b; Vita et al., 2024).

Third, the potential influence of primary study designs on the results should be considered. While most of the selected reviews included both RCTs and observational studies, two meta-analyses focused exclusively on RCTs (Kishi et al., 2016; Vita et al., 2024). RCTs often fail to show a benefit of LAIs over OAPs because of a selection bias favoring the inclusion of persons with less severe disorders and better medication adherence. This bias induces a ceiling effect that reduces the magnitude of the difference between LAIs and OAPs (Kane et al., 2013; Leucht et al., 2011; Verdoux et al., 2017). In contrast, most observational studies conducted in unselected participants favor LAIs over OAPs; this finding is also obtained by studies using statistical methods that control for confounding by indication.

Another concern is the potential influence of the pharmaceutical industry in the reviews, as most authors reported conflicts of interest. However, the sensitivity analysis performed in the meta-analysis by (Vita et al., 2024) showed similar results regarding relapse rates and acceptability of LAIs vs. OAPs, regardless of whether the individual articles were industry-sponsored or not.

## 4.3. Implications

In a recent systematic review, LAIs indications in EP was the only point where opposing recommendations were found (Correll et al., 2022a). Five guidelines mention LAIs use amongst the recommended strategies for people with EP (Association Française de Psychiatrie Biologique et de Neuropsychopharmacologie, Royal Australia New Zealand College of Psychiatrists, Texas Medication Algorithm Project, New Jersey Division of Mental Health Services, Florida Medicaid Program), while five others conclude that there is not enough data to support their early use (Singapore guidelines, National Institute for Health and Care Excellence, Scottish Intercollegiate Guidelines Network, British Association for Psychopharmacology, Schizophrenia Patient Outcome Research Team) (Correll et al., 2022a). In the light of this umbrella review, there is still not enough data to recommend LAIs over OAPs as a first-line treatment for people with EP. Considering the potential benefit of LAIs over OAPs regarding the discontinuation risk associated with treatment nonadherence in EP, this therapeutic strategy could be particularly useful for people with a poor medication adherence risk profile, such as comorbid substance use, lack of social support
or poor illness insight, as already suggested by some authors (Stip et al., 2019; Takeuchi et al., 2021).

LAIs should also be considered according to patients' preference (Stip et al., 2019; Takeuchi et al., 2021), as they showed similar efficacy and tolerance profile versus OAPs. Negative attitudes of clinicians could be a barrier to early LAIs use in clinical practice: a common opinion is that EP patients will not accept LAIs as they have never experienced a relapse (Kirschner et al., 2013). The acceptability of LAIs for people with EP remains elusive, as no information on users' attitude was identified in this umbrella review. Prescription of LAIs for EP patients with an uncertain diagnosis could be stigmatising and associated with negative perceptions (Kim et al., 2012). In this context, comprehensive information outlining the advantages and disadvantages of LAIs should be proposed to all people with EP. Establishing a therapeutic relationship with a shared decision-making process in medication choice may offer the opportunity to address the negative perceptions and stigma associated with LAIs (Kirschner et al., 2013). Future research should compare the impact of LAIs and OAPs on clinical improvement and relapse prevention in EP. Further evidence is needed to document the superiority of LAIs over OAPs in terms of discontinuation due to inefficacy or to medication nonadherence. Other potential benefits of LAIs compared to OAPs in EP were recently suggested by a large cohort study showing a 30% reduced risk of work disability (Solmi et al., 2022b). Further high-quality observational studies in real-life prescribing conditions are needed to support robust recommendations for clinical practice regarding LAIs indications in EP.

Supplementary data to this article can be found online at https://doi.org/10.1016/j.schres.2025.03.002.

## CRediT authorship contribution statement

**Marie Etienne:** Writing – review & editing, Writing – original draft, Project administration, Methodology, Investigation, Conceptualization.
**Hélène Verdoux:** Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Conceptualization.

## Funding sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

## Declaration of competing interest

The authors declare that there are no conflicts of interest in relation to the subject of this study.

## Acknowledgment

The authors thank Ray COOKE for copyediting the manuscript. They acknowledge the reviewers of a previous version of the manuscript for their thoughtful comments.

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