Sage Journals: Discover world-class research

Abstract

Background:

Long-acting injectable (LAI) antipsychotics are an important treatment option for the long-term treatment management of schizophrenia spectrum disorders (SSDs). Emerging evidences suggest a beneficial impact on long-term treatment outcomes, such as hospitalization and/or relapse risk.

Objectives:

We aimed to apply a 3-year follow-up mirror observation design to compare relapse as well as hospitalization rates and the number of hospitalization days during the 3 years before and after the start of LAI treatment in a sample of individuals with SSDs in a naturalistic outpatient clinical setting.

Methods:

We used a 3-year follow-up mirror-image design to compare hospitalization rates and duration, and the total number of clinical relapses in the 3 years before and after initiating LAI treatment in outpatients suffering from SSDs, switching from their oral counterparts.

Results:

Among 83 individuals screened, 56 adults (females, n = 20, 35.7%) with SSDs who began treatment with either first-generation (FGA) or second-generation (SGA) LAIs were included. Overall, switching from oral to LAI antipsychotic formulations significantly reduced both the number and duration of hospitalizations (from 10.15 to 0.18 average days) in treatment-compliant patients, as well as the overall number of relapses at 3 years of follow-up (from an average of 1.85 to 1.10). In the subgroup analysis, we found a reduced number of hospitalizations during the 3 years follow-up for both patients switched to SGA LAIs and FGA LAIs, but only if receiving LAI treatment for >6 consecutive months. This benefit was only reported in patients switched to LAI for the first time.

Conclusion:

This study highlights the effectiveness of LAIs as a maintenance treatment for SSDs, particularly for patients with longer LAI treatment duration. Future research may further identify the clinical characteristics of individuals with SSDs who may benefit most from LAI treatment.

Keywords

antipsychotic aripiprazole outpatients paliperidone palmitate recurrence

Introduction

In recent years, long-acting injectable antipsychotics (LAIs) have gained a crucial role in the management of schizophrenia spectrum disorders (SSDs).^1–3 The increasing role of LAI owes to multiple factors: cost reduction, development of new molecules accessible as LAI formulations, availability of the same molecules but with a longer injection interval, and finally to a change in the attitudes of clinicians, patients and caregivers, with the possibility of early prescription of LAIs, experienced as an opportunity rather than a constriction.^4,5

The effectiveness of antipsychotic drugs in LAI formulation is demonstrated in numerous clinical studies, observational data, and robust meta-analyses.^6–8 One obvious clinical benefit is related to better adherence compared to their oral counterparts.⁹ Apart from the improved adherence, LAIs demonstrate more stable pharmacokinetic patterns related to better antipsychotic exposure.¹⁰ Moreover, clinical data indicate several positive consequences of the switch from oral antipsychotics to LAI therapy that escape classic pharmacokinetic or clinical efficacy evaluation, but which are equally important for patients and their caregivers.^11–13 Switching from oral antipsychotics to LAI formulations has demonstrated not only symptom improvement but also lasting advantages in areas such as tolerability, cognitive function, and treatment acceptance, with outcomes linked to notable enhancements in clinical effects over the long term.^14–16 Moreover, emerging literature suggests a beneficial impact of a switch from oral to LAI antipsychotics in terms of quality of life, work and daily functioning, perceived stigma and self-stigma, life expectancy, and use of health care facilities and emergency visits, as well as overall personal and health system costs.^8,17,18

In this study, we aimed to apply a 3-year follow-up mirror observation design to compare relapse as well as hospitalization rates and the number of hospitalization days during the 3 years before and after the start of LAI treatment in a sample of individuals with SSDs in a naturalistic outpatient clinical setting. In fact, based on the previous literature,¹⁹ we hypothesize that switching to LAI in SSDs would have a positive impact on clinical course, especially in patients with longer observation time windows before and after the switch to LAIs.

Methods

Study design

We conducted a naturalistic observational mirror-image study to compare the likelihood of hospitalization within a 3-year period before and after initiating maintenance treatment with an LAI in adults suffering from SSDs. The initiation date of LAI treatment served as the index timepoint for study inclusion. Clinical information was collected through medical records and through not-recorded interviews, after collecting patients’ written informed consents.

Participants were consecutively recruited and followed up at the Psychiatry Unit of the University Hospital Magna Graecia in Catanzaro, Italy, between January 2021 and January 2025, collecting data up to 3 years before enrollment. Eligibility criteria included the following: (1) age between 18 and 65 years, with the capacity to provide informed consent; (2) a diagnosis of SSDs confirmed by a senior psychiatrist according to DSM-5 criteria; (3) stabilization on oral first-generation antipsychotic (FGA) (e.g., haloperidol) or second-generation antipsychotic (SGA) therapy, also available in LAI formulations (i.e., aripiprazole and paliperidone), for at least 6 months prior to enrollment; and (4) absence of substance abuse or dependence for the past 6 and 12 months, respectively.

Exclusion criteria included: (1) a recent (within 12 months) or uncertain diagnosis of SSDs; (2) the presence of any other major psychiatric disorder as defined by DSM-5 criteria; (3) undocumented medical history; and (4) a history of medical or neurological conditions that could impair cognitive functioning.

The study outcomes were: (1) hospitalization rates and relapse number, assessed by comparing the 3 years before and the 3 years after the switch to LAI treatment, and (2) the total number of hospitalization days, evaluated by the difference between these two periods (oral vs LAI).

Measures

A standardized form was used to gather sociodemographic (e.g., age, sex, education, marital status), clinical (e.g., diagnosis, number and duration of hospitalizations in the past 3 years, alcohol/substance-related disorders, metabolic comorbidities), and pharmacological information (e.g., current and prior treatments, prescribed LAI, side effects). Data were collected through clinical interviews, study of health records, and chart reviews to establish participants’ baseline and follow-up characteristics (see Supplementary material Table 2). A follow-up form was utilized to document treatment details, including the date and reasons for LAI discontinuation, using a checklist. Relapse was defined as an increase of ⩾12 points in the positive and negative syndrome scale (PANSS) total score, used in its Italian validated version,²⁰ or worsening of specific positive and disorganization symptom items.²¹

This study adhered to the guidelines outlined in the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement (see supplementary material Table 1).²² Standard pharmacovigilance protocols for monitoring potential adverse drug reactions in routine clinical practice were implemented, following the recommendations of the national regulatory agency (AIFA) (https://www.aifa.gov.it/en/). The study protocol received approval from the local ethics committees of the participating center. The research complied with the ethical principles of the Declaration of Helsinki for medical research involving human subjects.²³

Statistical analysis

Descriptive statistics were employed for summarizing the data. Changes in hospitalization rates between the 3-year period before and after LAI administration were analyzed using McNemar’s test, with chi-square (χ²) and p-values estimated. Additionally, changes in relapse rates between the pre- and post-LAI periods were assessed using a paired-sample t-test, with mean differences and corresponding p-values reported.

Analyses were stratified by the following factors: (1) continuation or discontinuation of LAI treatment, with discontinuers defined as those receiving LAI treatment for fewer than 6 consecutive months; (2) class of LAI prescribed, distinguishing between SGA and FGA; (3) previous treatment with LAI treatment (before study start), differentiating novel LAI users from those previously treated with LAIs; (4) concurrent treatment with psychotropic agents (other than LAI), including oral antipsychotics (agents distinct from the active compound of the LAI) or mood stabilizers (lithium or antiseizure medications). All analyses were adjusted for age, sex, and comorbid alcohol or substance use disorders. The sample size was not calculated, as this was a real-world observational study that enrolled all consecutive patients attending the Psychiatry Unit. Statistical significance was set at p < 0.05, and data analysis was performed using the Statistical Package for Social Sciences Version 25 (SPSS, Chicago, IL, USA).

Results

Study participants

Initially, 83 patients were screened for the study; however, 27 were excluded for various reasons:15 either lacked interest in participating or were illiterate, 10 withdrew before completing treatment, and 2 withdrew because of missing data. Specifically, seven patients before starting the LAI switch and three from the LAI treatment phase dropped out. Regarding participants who stopped LAI treatment, two of them have been prescribed aripiprazole monohydrate, and one has been prescribed paliperidone palmitate and dropped the protocol because of non-adherence. In the oral treatment phase, six patients discontinued due to lack of clinical response or due to non-adherence, and one due to relocation. As a result, the final sample consisted of 56 participants (Figure 1).

Figure 1.

Participants’ flow-chart on the inclusion process.

Table 1 shows the sociodemographic and clinical features of the sample (n = 56, mean age of 42.6 ± 14.5 years, 35.7% females). Noteworthy, 55.4% (N = 31) of the participants were smokers, while 44.6% (N = 25) were non-smokers. Moreover, a majority of the sample (71.4%, N = 40) received LAI antipsychotics for the first time, while 28.6% (N = 16) had prior exposure to LAI treatment. The mean duration of treatment was 14.1 years (SD = 9.1).

Table 1.

Sociodemographic and clinical characteristics of the sample.

Variable		N = 56
Variable		Fr	%
Mean age (years)^a		42.6	(14.5)
Sex	Male	36	(64.3)
	Female	20	(35.7)
Civil status	Married	9	(16.1)
	Divorced	5	(8.9)
	Single	42	(75.0)
Ethnicity	Caucasian	52	(92.9)
	Black	4	(7.1)
Education (years)^a		11.6	(3.5)
Employment	Employed	13	(23.2)
	Unemployed	16	(28.6)
	On pension	4	(7.1)
	Unpaid activity	10	(17.9)
	Invalid/Retired	13	(23.2)
Smoker	Yes	31	(55.4)
	No	25	(44.6)
First LAI ever	Yes	40	(71.4)
	No	16	(28.6)
Treatment duration (years)^a		14.1	(9.1)
At least one concomitant mood stabilizer		34	(60.7)
	Lithium	11	(19.6)
	Anticonvulsants	23	(41.1)
At least one concomitant antidepressant		24	(42.9)
At least one concomitant benzodiazepine		31	(55.4)

Data are expressed as means and (standard deviation).

LAI, long-acting injectable.

Regarding concomitant psychotropic medication use, 60.7% (N = 34) of participants were prescribed at least one mood stabilizer. Among them, 19.6% (N = 11) received lithium, while 41.1% (N = 23) were prescribed antiseizure medications. In addition, 42.9% (N = 24) of the participants were taking at least one antidepressant, and 55.4% (N = 31) were prescribed at least one benzodiazepine.

Hospitalization rates: Mirror‑image analyses

Table 2 presents hospitalization rates over a 3-year period before and after the switch to LAI. The overall hospitalization rates significantly decreased from 32.1% (N = 18/56) before treatment to 5.4% (N = 3/56) after treatment (p < 0.001).

Table 2.

Effects of LAI treatment on hospitalization rates: Mirror-image analysis.

Individuals with at least one hospitalization after 3 years of treatment compared to 3 years before LAI initiation
	Pre-LAI (%)	Post-LAI (%)	McNemar	p
Overall (N = 56)	18/56 (32.1)	3/56 (5.4)	13.474	<0.001
Continuers (N = 42)	15/42 (35.7)	1/42 (2.4)	10.563	0.001
Discontinuers (N = 14)	4/14 (28.6)	1/14 (7.1)	2.250	0.125
SGA LAI (N = 45)	15/45 (33.3)	1/45 (2.2)	10.563	0.001
FGA LAI (N = 11)	10/11 (90.9)	1/11 (9.1)	5.818	0.012
First-ever LAI (N = 40)	17/40 (42.5)	1/40 (2.5)	13.474	<0.001
Previous LAI users (N = 16)	1/16 (6.25)	1/16 (6.25)	0.0	1.000
Concomitant oral SGA/FGA (N = 15)	6/15 (15.0)	1/15 (6.7)	4.167	0.031
No oral SGA/FGA (N = 41)	12/41 (28.6)	2/41 (4.9)	7.692	0.003
Concomitant mood stabilizer (N = 33)	15/33 (45.5)	2/33 (6.1)	13.067	<0.001
Concomitant antidepressant (N = 22)	9/22 (40.9)	2/22 (9.1)	4.900	0.021
Concomitant benzodiazepines (N = 21)	4/21 (19.0)	2/21 (9.5)	2.250	0.125

Boldface indicates statistical significance. Continuers: Patients receiving LAI treatment for the whole 3 years of observational time. Discontinuers: Patients receiving LAI treatment for fewer than six consecutive months.

FGA, first-generation antipsychotic; LAI, long-acting injectable; SGA, second-generation antipsychotic.

Among continuers (those who remained on LAI treatment), hospitalization rates dropped from 35.7% (N = 15/42) to 2.4% (N = 1/42) (p = 0.001), whereas among discontinuers, the reduction from 28.6% (N = 4/14) to 7.1% (N = 1/14) was not statistically significant (p = 0.125).

When stratifying for the type of LAI, both SGA LAIs and FGA LAIs were associated with a significant reduction in hospitalization rates, from 33.3% (N = 15/45) to 2.2% (N = 1/45, p = 0.001) for SGA LAIs, and from 31.3% (N = 10/32) to 3.1% (N = 1/32, p = 0.012) for FGA LAIs. Similarly, individuals receiving LAI treatment for the first time showed a significant decline in hospitalization rates, from 42.5% (N = 17/40) to 2.5% (N = 1/40, p < 0.001). Hospitalization rates were not affected in patients who had already used LAI in the past (N = 1/16, p = 1.00) for both of them (p = 1.000)

A significant reduction in hospitalization rates was also observed in individuals receiving concomitant oral SGA/FGA (15.0% to 6.7%, p = 0.031) and those with no oral SGA/FGA use (28.6% to 4.9%, p = 0.003). In addition, patients on mood stabilizers experienced a significant decline, from 45.5% (N = 15/33) to 6.1% (N = 2/33) (p < 0.001), as did those taking antidepressants (40.9% to 9.1%, p = 0.021). However, the decrease in hospitalization rates among patients using benzodiazepines (19.0%–9.5%) was not statistically significant (p = 0.125).

Relapse rates: Mirror‑image analyses

Table 3 summarizes hospitalization rates over a 3-year span before and after the switch to LAI treatment. Overall, the relapse rate dropped significantly from 85.7% (48 out of 56 patients) prior to treatment to 66.1% (37 out of 56) following the switch (p = 0.013).

Table 3.

Effects of LAI treatment on relapse rates: mirror-image analysis.

Individuals with at least one relapse after 3 years of treatment compared to 3 years before LAI initiation
	Pretreatment (%)	Post-treatment (%)	McNemar	p
Overall (N = 56)	48/56 (85.7)	37/56 (66.1)	5.882	0.013
Continuers (N = 42)	35/42 (83.3)	27/42 (64.3)	3.500	0.057
Discontinuers (N = 14)	13/14 (92.8)	10/14 (71.4)	1.333	0.250
SGA LAI (N = 45)	37/45 (82.2)	30/45 (66.7)	2.769	0.092
FGA LAI (N = 32)	28/32 (87.5)	18/32 (56.2)	6.750	0.006
First-ever LAI (N = 40)	34/40 (85.0)	26/40 (65.0)	4.083	0.039
Previous LAI users (N = 16)	14/16 (87.5)	11/16 (68.8)	0.800	0.375
Concomitant oral SGA/FGA (N = 15)	13/15 (86.7)	12/15 (80.0)	0.000	1.000
No oral SGA/FGA (N = 41)	35/41 (85.4)	25/41 (61.0)	5.786	0.013
Concomitant mood stabilizer (N = 33)	31/33 (93.9)	25/33 (75.8)	2.500	0.109
Concomitant antidepressant (N = 22)	21/22 (95.4)	17/22 (77.3)	1.500	0.219
Concomitant benzodiazepines (N = 21)	18/21 (85.7)	13/21 (61.9)	1.455	0.227

Boldface indicates statistical significance. Continuers: Patients receiving LAI treatment for the whole 3 years observational time. Discontinuers: Patients receiving LAI treatment for fewer than 6 consecutive months.

FGA, First-generation antipsychotic; LAI, Long-acting injectable; SGA, Second-generation antipsychotic.

Considering patients who continued with LAI therapy, relapse rates decreased, although not reaching statistical significance, from 83.3% (35/42) to 64.3% (27/42) (p = 0.057). On the other hand, those who discontinued LAI treatment showed a less marked, nonsignificant reduction in relapse rates compared to continuers, declining from 92.8% (13/14) to 71.4% (10/14) (p = 0.250).

When analyzing by LAI type, both SGA and FGA LAIs were linked to relevant reductions of relapse rates, although only treatment with FGA reached statistical significance. Specifically, relapse rates for SGA LAIs fell from 82.2% (37/45) to 66.7% (30/45, p = 0.092), while FGA LAIs showed a decline from 87.5% (28/32) to 56.2% (18/32, p = 0.006).

Patients initiating LAI treatment for the first time experienced a significant drop in relapse rates, from 85.0% (34/40) to 65.0% (26/40, p < 0.039). Conversely, no significant change was observed among patients who had previously been treated with LAIs, from 87.5% (14/16) to 68.8% (11/16), before and after the switch (p = 0.375).

No significant change in relapse rates was reported in patients receiving concomitant oral SGAs/FGAs (from 86.7% to 80.0%, p = 1.000), while there was a reduction in relapse rates in patients not using concomitant oral SGAs/FGAs (from 85.4% to 61.0%, p = 0.013).

Finally, patients receiving comedication with mood stabilizers had relapse rates reduced from 93.9% (31/33) to 75.8% (25/33) (p = 0.109), and patients receiving comedication with antidepressants had a decrease of relapse events from 95.4% (21/22) to 73.3% (17/22) (p = 0.219). However, the reduction among patients with comedication with benzodiazepines, from 85.7% (18/21) to 61.9% (13/21), was not statistically significant (p = 0.227).

Hospitalization days and relapse rates before and after LAI initiation: Mirror‑image analyses

Mirror-image analyses comparing the 3-year periods before and after the initiation of LAI treatment are reported in Table 3 and revealed a significant reduction in the total number of hospitalization days as well as total number of relapses following the switch from oral to LAI formulation (t = 2.006, p = 0.050 and t = 2.849, p = 0.006) (Table 4).

Table 4.

Effects of LAI treatment on hospitalization days and relapse rates: Mirror-image analysis.

Variable		Mean	SD	n	t	p
Hospitalization days	3 years before LAI	10.25	37.57	56	2.006	0.050
	3 years after LAI	0.18	1.34	56
Relapses	3 years before LAI	1.85	1.82	52	2.849	0.006
	3 years after LAI	1.10	1.19	52

LAI, long-acting injectable; SD, standard deviation; t, t-test.

Bold characters indicate statistical significance.

Discussion

This study prospectively evaluated the effectiveness of LAIs in individuals with SSDs in real-world outpatient settings in Italy with a 3-year observational follow-up period and a mirror-image study design. Our research yielded three key findings. First, LAIs were significantly associated with a reduction in hospitalization rates and duration, and overall relapse rates, aligning with existing evidence.^24,25

Our findings align with previous real-world, mirror-image studies on LAIs in SSDs, which suggest reduced hospitalizations following treatment initiation with aripiprazole monohydrate, paliperidone palmitate, risperidone LAI, or other LAIs.^26–29 This reduction is likely due to improved medication adherence, which helps prevent psychotic relapses and hospitalizations. Among SGA LAIs, risperidone, paliperidone, and aripiprazole are considered the most effective alternatives to oral medications.^3,30 However, more recently, risperidone in situ microspheres (ISM^®, Laboratorios Farmacéuticos ROVI, S.A. (ROVI), Madrid, Spain) LAI appears to prevent psychotic symptoms compared with adequate tolerability,^31,32 while aripiprazole monohydrate once-bimonthly significantly delays psychotic episode recurrence without triggering secondary adverse drug reactions.³³ Therefore, these two newest different formulations of already well-known drugs (i.e., risperidone ISM^® and aripiprazole monohydrate once-bimonthly) represent promising therapeutic options providing enhanced pharmacokinetic properties and extended dosing intervals, which may better support adherence and improved key clinical outcomes.^34–36

FGA LAIs are also effective in preventing psychotic episodes and hospitalizations, though they show a limited safety and tolerability profile, especially in the long-term and for younger and first-episode patients.^3,37,38 Indeed, interestingly, both FGA and SGA LAIs demonstrated efficacy in reducing hospitalization, albeit with different numbers of participants. This data are not surprising, since even the most modern reviews do not question the clinical efficacy of FGA LAIs, if anything, what is of concern is their tolerability and safety in the long term, which is why SGA LAIs appear to be a more suitable choice for a long-term management strategy.^30,39

An additional key finding with important clinical relevance is that the impact of LAI treatment on clinical outcomes appears to be consistent across both FGA and SGA agents. Thus, these overall benefits suggest a formulation effect rather than a drug-specific effect, and this likely stems from improved treatment adherence rather than the properties of a particular drug.^4,40 Further supporting this, positive outcomes were observed mainly in individuals who consistently adhered to LAI treatment, while those who discontinued experienced similar but reduced benefits—suggesting, however, that reducing the initial risk of hospitalization represents a protective factor despite subsequent discontinuation of LAI therapy. This finding could be explained by the overall protective effect of antipsychotic treatment on the prognosis of SSDs, an advantage that becomes more evident the earlier the therapy is taken continuously and the shorter the duration of untreated illness.^41,42 Indeed, the lack of clinical response in the first weeks of illness is generally considered a negative prognostic factor for psychosis, whereas timely and sustained therapy with significant reduction in positive and negative symptoms is associated with a lower risk of treatment resistance, regardless of the treatment used.^43–45

Second, in our data, we highlighted efficacy aspects in patients using LAI therapy for the first time. This greater impact of LAI treatment in previously unexposed patients could have both a conceptual and a practical explanation. In fact, in recent years, the use of LAIs has gone from being a last-line prescription in noncompliant patients to a valid therapeutic alternative in young patients at the first episode, who have not yet developed a pharmacological resistance.^46–48 Furthermore, considering that SGA LAI formulations are limited to four molecules (i.e., aripiprazole, olanzapine, paliperidone, and risperidone), having failed one or more LAI treatments greatly reduces the number of options still available.^3,49 Interpreting our results further reinforces the idea that early use of LAI antipsychotic therapy can have a tangible impact in modifying the trajectory of the illness. Indeed, the reduction in hospitalization and relapse rates, especially in first-time LAI users, places this therapeutic option at the forefront of clinicians’ choices.^38,50,51 Therefore, the key point is that the initial benefit of LAI treatment mainly comes from improving adherence—once patients start LAIs, better adherence leads to fewer hospitalizations. However, for patients who have already been on LAIs but still experience psychotic episodes, the issue likely extends beyond adherence to treatment resistance. In such cases, LAIs alone may offer limited benefit, and alternative treatments such as clozapine may be required.^10,52,53

On the other hand, treatment with FGA versus SGA does not seem to differ regarding hospitalization risk, while the relapse risk seems to be reduced with the FGA LAI. This result only partially contrasts with the findings of Tiihonen’s research conducted in the nationwide Finnish cohort study. Indeed, authors concluded that while FGAs are more effective in treating positive symptoms such as hallucinations and delusions, SGAs are often associated with better outcomes in terms of relapse-free survival, psychiatric hospitalization rates, and treatment adherence, with data reported for both oral and LAI administration.⁵⁴ This difference could be explained by both the different sample size compared to a study using a national register, but also by the methodology used in our work. Our sample included haloperidol as FGA LAI and aripiprazole and paliperidone as SGA LAI, while we did not manage cases with perphenazine, olanzapine, and risperidone. Specific studies for different molecules could provide different results.^55,56

In addition, we did not report differences in relapse rates between patients with LAI antipsychotic monotherapy versus patients receiving comedication with oral antipsychotics. Focusing on hospitalization rates, there was a statistically significant reduction for both patients taking (p = 0.031) or not a second oral antipsychotic (p = 0.003). This data should be interpreted considering that, usually, a second antipsychotic is started or maintained in case of an aborted switch.⁵⁷ Therefore, we could speculate that patients taking a combination of at least two antipsychotics reflect a more severe and less responsive to treatment subgroup. Therefore, it is precisely on this subgroup that the LAI formulations may be less effective, but this may not be related to the drug formulation but to the greater pharmacological resistance or chronicity of the disease.⁵⁸

Our results also identified a direct efficacy of LAI antipsychotic therapy on the number of clinical relapses compared to previous oral therapy. This finding is not surprising, since other similar studies have confirmed, albeit with different research designs, that the use of the LAI formulation prevents psychotic exacerbations more than their oral counterparts.^59–61 Moreover, a recent systematic review and individual participant data meta-analysis of clinical trials of LAIs for psychosis relapse-prevention conclude that LAI treatment might not prevent clinical relapses for patients not adequately stabilized on continuous antipsychotic treatment.⁶² This same trend seems to emerge from our results, where the most severe relapses (therefore associated with hospitalization) are effectively reduced with the switch to LAI treatment.

Limitations

When evaluating the results of this research, some methodological limitations should also be considered. First, although our sample size was comparable to similar studies, it remained relatively limited, and it would be desirable to replicate similar results with a larger sample size.^63–66 Moreover, we did not calculate in advance the sample size, and this may limit the interpretation. Regarding hospitalization risk, switching to the LAI formulation appears to be more effective in continuers and in patients taking LAI treatment for the first time. It would have been interesting to investigate the demographic and clinical characteristics of the continuers, to better understand whether the choice to continue or not LAI therapy depends on intrinsic characteristics of the drug, the disease, the patient, or the health care facility. Several authors have previously proposed that poor adherence to LAI antipsychotics may be influenced by factors such as adverse events—especially sexual, metabolic, and extrapyramidal side effects—insufficient treatment efficacy, symptom severity (notably in areas like suspiciousness and hostility), negative attitudes toward medication or LAI formulation, treatment-related stigma, cognitive impairments, co-occurring substance use disorders, patients’ age, and limited insight into the illness.^67–69

Second, we were unable to investigate the impact of specific SSD features, such as the age at onset, prevalent symptom profiles, and prior treatment episodes—known to particularly benefit from LAI treatment or other clinical characteristics.^70–72 Third, we were unable to analyze the comparative effects of the type of LAI in relation to other crucial factors influencing the clinical course of SSDs, such as neurocognition, psychosocial functioning, comorbid conditions, and addictive behaviors.

Conclusion

Our study supports the role of LAIs in reducing hospitalization rates and duration, as well as relapse rate, over a 3-year follow-up period. Therefore, LAIs may serve as the mainstay of treatment for SSDs in the long term. However, further research—preferably involving larger samples and more structured assessments—is needed to identify the clinical characteristics of individuals with SSDs who would benefit most from long-acting antipsychotic formulations.

Supplemental Material

sj-docx-1-tpp-10.1177_20451253251403263 – Supplemental material for Impact of treatment with long-acting injectable antipsychotics on hospitalization and relapse rates in schizophrenia spectrum disorders: a 3-year follow-up mirror-image study

Supplemental material, sj-docx-1-tpp-10.1177_20451253251403263 for Impact of treatment with long-acting injectable antipsychotics on hospitalization and relapse rates in schizophrenia spectrum disorders: a 3-year follow-up mirror-image study by Renato de Filippis, Matteo Aloi, Alfredo Cimino, Elvira Anna Carbone, Marianna Rania, Ettore D’Onofrio, John M. Kane, Georgios Schoretsanitis, Cristina Segura-Garcia and Pasquale De Fazio in Therapeutic Advances in Psychopharmacology

Supplemental Material

sj-docx-2-tpp-10.1177_20451253251403263 – Supplemental material for Impact of treatment with long-acting injectable antipsychotics on hospitalization and relapse rates in schizophrenia spectrum disorders: a 3-year follow-up mirror-image study

Supplemental material, sj-docx-2-tpp-10.1177_20451253251403263 for Impact of treatment with long-acting injectable antipsychotics on hospitalization and relapse rates in schizophrenia spectrum disorders: a 3-year follow-up mirror-image study by Renato de Filippis, Matteo Aloi, Alfredo Cimino, Elvira Anna Carbone, Marianna Rania, Ettore D’Onofrio, John M. Kane, Georgios Schoretsanitis, Cristina Segura-Garcia and Pasquale De Fazio in Therapeutic Advances in Psychopharmacology

Footnotes

Acknowledgements

The authors express gratitude to the participants who took part in the study.

Declarations

Ethics approval and consent to participate

Before data collection, the study protocol underwent review and approval by the local Ethical Committee of University Hospital Mater Domini of Catanzaro (Italy), “Regione Calabria, sezione Area Centro” (n. 191/2020), and patients’ written informed consents were collected.

Consent for publication

Patients’ informed consents have been collected.

Author contributions

Renato de Filippis: Conceptualization; Data curation; Methodology; Writing – original draft; Writing – review & editing.

Matteo Aloi: Methodology; Writing – review & editing.

Alfredo Cimino: Data curation.

Elvira Anna Carbone: Data curation; Writing – review & editing.

Marianna Rania: Data curation; Writing – review & editing.

Ettore D’Onofrio: Data curation.

John M. Kane: Writing – review & editing.

Georgios Schoretsanitis: Writing – review & editing.

Cristina Segura-Garcia: Supervision; Writing – review & editing.

Pasquale De Fazio: Supervision; Writing – review & editing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Competing interests

In the last 3 years, Dr. de Filippis has received speaker fees from Angelini, Johnson & Johnson, Lundbeck, Neuraxpharm, and Rovi and travel support from Angelini, Johnson & Johnson, Lundbeck, Otsuka, and Rovi. All other authors declare no competing interests. Dr. Kane has been a consultant for or received honoraria from AbbVie, Alkermes, BMS, Boehringer Ingelheim, Cerevel, Click, Dainippon Sumitomo, H Lundbeck HLS Therapeutics, Intra-Cellular Therapies, Janssen, Johnson & Johnson, Karuna Therapeutics, LB Pharmaceuticals, Lyndra Therapeutics, Maplight Therapuetics, Merck, Neurocrine Biosciences, Newron, NW PharmaTech, Otsuka, Reviva Pharmaceuticals, Roche, Saladax Biomedical, Sunovion, Takeda, and Teva Pharmaceuticals; has received grant support from Otsuka, Lundbeck, Merck, and Janssen; and is a shareholder of LB Pharmaceuticals, Medincell, and Vanguard Research Group. Dr. Schoretsanitis has served as a consultant for Dexcel Pharma, HLS Therapeutics, Saladax, and Thermo Fisher and has received speaker fees from HLS Therapeutics, Lundbeck, and Saladax. Other authors declare no conflict of interest.

Availability of data and materials

The data that support the findings of this study are available on request from the corresponding author.

ORCID iDs

Renato de Filippis

Matteo Aloi

Elvira Anna Carbone

Cristina Segura-Garcia

Supplemental material

Supplemental material for this article is available online.

References

Patel

Saxena

Lund

, et al. The lancet commission on global mental health and sustainable development. Lancet 2018; 392: 1553–1598.

Sugawara

Kudo

Ishioka

, et al. Attitudes toward long-acting injectable antipsychotics among patients with schizophrenia in Japan. Neuropsychiatr Dis Treat 2019; 15: 205–211.

de Filippis

De Fazio

Gaetano

, et al. Current and emerging long-acting antipsychotics for the treatment of schizophrenia. Expert Opin Drug Saf 2021; 20: 771–790.

Kane

Rubio

JM.

The place of long-acting injectable antipsychotics in the treatment of schizophrenia. Ther Adv Psychopharmacol 2023; 13: 204512532311572.

D’Agostino

Aguglia

Barbui

, et al. Off–label long acting injectable antipsychotics in real–world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study. BMC Psychiatry 2022; 22: 442.

Llorca

Abbar

Courtet

, et al. Guidelines for the use and management of long-acting injectable antipsychotics in serious mental illness. BMC Psychiatry 2013; 13: 340.

de Filippis

Staltari

Aloi

, et al. Effectiveness of SGA-LAIs on clinical, cognitive, and social domains in schizophrenia: results from a prospective naturalistic study. Brain Sci 2023; 13: 577.

Kishimoto

Hagi

Kurokawa

, et al. Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre–post studies. Lancet Psychiatry 2021; 8: 387–404.

Titus-Lay

Ansara

Isaacs

, et al. Evaluation of adherence and persistence with oral versus long-acting injectable antipsychotics in patients with early psychosis. Ment Heal Clin 2018; 8: 56–62.

10.

Brissos

Veguilla

Taylor

, et al. The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal. Ther Adv Psychopharmacol 2014; 4: 198–219.

11.

Robinson

Suett

Wilhelm

, et al. Patient and healthcare professional preferences for characteristics of long-acting injectable antipsychotic agents for the treatment of schizophrenia. Adv Ther 2023; 40: 2249–2264.

12.

Blackwood

Sanga

Nuamah

, et al. Patients’ preference for long-acting injectable versus oral antipsychotics in schizophrenia: results from the patient-reported medication preference questionnaire. Patient Prefer Adherence 2020; 14: 1093–1102.

13.

Mace

Chak

Punny

, et al. Positive views on antipsychotic long-acting injections: results of a survey of community patients prescribed antipsychotics. Ther Adv Psychopharmacol 2019; 9: 204512531986097.

14.

Pietrini

Spadafora

Talamba

, et al. The effects of switching from oral to LAI antipsychotic treatment on subjective experience of schizophrenic and schizoaffective patients: preliminary results. Int J Psychiatry Clin Pract 2015; 19: 106–113.

15.

Pietrini

D’Anna

Tatini

, et al. Changes in attitude towards LAI antipsychotic maintenance treatment: a two-year follow-up study. Eur Psychiatry 2018; 53: 58–65.

16.

Pietrini

Tatini

Santarelli

, et al. Self- and caregiver-perceived disability, subjective well-being, quality of life and psychopathology improvement in long-acting antipsychotic treatments: a 2-year follow-up study. Int J Psychiatry Clin Pract 2021; 25: 307–315.

17.

Milz

Benson

Knight

, et al. The effect of longer dosing intervals for long-acting injectable antipsychotics on outcomes in schizophrenia. Neuropsychiatr Dis Treat 2023; 19: 531–545.

18.

Okoli

CTC

Kappi

Wang

, et al. The effect of long-acting injectable antipsychotic medications compared with oral antipsychotic medications among people with schizophrenia: a systematic review and meta-analysis. Int J Ment Health Nurs 2022; 31: 469–535.

19.

Kappi

Wang

Abu Farsakh

, et al. 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. J Am Psychiatr Nurses Assoc 2025; 31: 138–164.

20.

Pancheri

Brugnoli

Pancheri

, et al. Valutazione dimensionale della sintomatologia schizofrenica. Validazione della versione italiana della Scala per la valutazione dei Sintomi Positivi e Negativi (PANSS). Giorn Ital Psicopat 1995; 60: 1–3.

21.

Siafis

Brandt

McCutcheon

, et al. Relapse in clinically stable adult patients with schizophrenia or schizoaffective disorder: evidence-based criteria derived by equipercentile linking and diagnostic test accuracy meta-analysis. Lancet Psychiatry 2024; 11: 36–46.

22.

von Elm

Altman

Egger

, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol 2008; 61: 344–349.

23.

World Medical Association. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310: 2191.

24.

Sancho-Echeverria

Aymerich

Rodríguez-Sánchez

, et al. Effect of long-acting antipsychotic treatment on psychiatric hospitalization rate in early psychosis patients: a naturalistic study. Ther Adv Psychopharmacol 2024; 14: 20451253241243270.

25.

Correll

Benson

Emond

, et al. Comparison of clinical outcomes in patients with schizophrenia following different long-acting injectable event-driven initiation strategies. Schizophrenia 2023; 9: 9.

26.

Geng

Benson

, et al. Real-world effectiveness of long-acting injectable and oral antipsychotic agents in US medicare patients with schizophrenia. Adv Ther 2025; 42: 1251–1264.

27.

Boyer

Falissard

Nuss

, et al. Real-world effectiveness of long-acting injectable antipsychotic treatments in a nationwide cohort of 12,373 patients with schizophrenia-spectrum disorders. Mol Psychiatry 2023; 28: 3709–3716.

28.

Peitl

Margetić

Vidrih

, et al. The impact of long-acting paliperidone in reducing hospitalizations and clinical severity in recent onset schizophrenia: a mirror-image study in real-world clinical setting. Clin Psychopharmacol Neurosci 2022; 20: 118–125.

29.

Vincent

Demers

M-F

Doyon-Kemp

, et al. One year mirror-image study using paliperidone palmitate for relapse prevention of schizophrenia in four university hospitals in Canada. Schizophr Res 2017; 185: 96–100.

30.

Vita

Pollini

Canozzi

, et al. Efficacy and acceptability of long-acting antipsychotics in acutely ill individuals with schizophrenia-spectrum disorders: a systematic review and network meta-analysis. Psychiatry Res 2024; 340: 116124.

31.

Álamo

Risperidone ISM as a new option in the clinical management of schizophrenia: a narrative review. Adv Ther 2022; 39: 4875–4891.

32.

Schoretsanitis

Correll

CU.

Pharmacokinetic characteristics of risperidone ISM for the treatment of schizophrenia. Expert Opin Drug Metab Toxicol 2025; 21: 1–9.

33.

Harlin

Yildirim

Such

, et al. A randomized, open-label, multiple-dose, parallel-arm, pivotal study to evaluate the safety, tolerability, and pharmacokinetics of aripiprazole 2-month long-acting injectable in adults with schizophrenia or bipolar I disorder. CNS Drugs 2023; 37: 337–350.

34.

Bartoli

Cavaleri

Riboldi

, et al. Clinical utility of long-acting injectable risperidone in schizophrenia and bipolar I disorder: a review of clinical studies. Psychol Res Behav Manag 2025; 18: 1455–1469.

35.

de Filippis

D’Onofrio

Liparota

, et al. The place of risperidone in situ microparticles (ISM®) among long-acting injectable antipsychotics in schizophrenia treatment. Expert Opin Pharmacother 2025; 26(13): 1379–1397.

36.

Baune

BT.

Aripiprazole 2-month ready-to-use 960 mg (Ari 2MRTU): review of its possible role in schizophrenia therapy. Curr Med Res Opin 2024; 40: 87–96.

37.

Ostuzzi

Mazzi

Terlizzi

, et al. Factors associated with first- versus second-generation long-acting antipsychotics prescribed under ordinary clinical practice in Italy. PLoS One 2018; 13: e0201371.

38.

Kane

Schooler

Marcy

, et al. Effect of long-acting injectable antipsychotics vs usual care on time to first hospitalization in early-phase schizophrenia. JAMA Psychiatry 2020; 77: 1–8.

39.

Pilon

Joshi

Tandon

, et al. Treatment patterns in Medicaid patients with schizophrenia initiated on a first- or second-generation long-acting injectable versus oral antipsychotic. Patient Prefer Adherence 2017; 11: 619–629.

40.

Correll

Kim

Sliwa

, et al. Pharmacokinetic characteristics of long-acting injectable antipsychotics for schizophrenia: an overview. CNS Drugs 2021; 35: 39–59.

41.

Karson

Duffy

Eramo

, et al. Long-term outcomes of antipsychotic treatment in patients with first-episode schizophrenia: a systematic review. Neuropsychiatr Dis Treat 2016; 12: 57–67.

42.

Harrow

Jobe

Faull

, et al. A 20-Year multi-followup longitudinal study assessing whether antipsychotic medications contribute to work functioning in schizophrenia. Psychiatry Res 2017; 256: 267–274.

43.

Correll

Malhotra

Kaushik

, et al. Early prediction of antipsychotic response in schizophrenia. Am J Psychiatry 2003; 160: 2063–2065.

44.

Correll

Rubio

Kane

JM.

What is the risk-benefit ratio of long-term antipsychotic treatment in people with schizophrenia?

World Psychiatry 2018; 17: 149–160.

45.

Panov

GP.

Early markers in resistant schizophrenia: effect of the first antipsychotic drug. Diagnostics 2022; 12: 803.

46.

Kane

Chen

Lim

, et al. Early versus late administration of long-acting injectable antipsychotic agents among patients with newly diagnosed schizophrenia: an analysis of a commercial claims database. Int Clin Psychopharmacol 2023; 38: 240–248.

47.

Bertolini

Ostuzzi

Pievani

, et al. Comparing long-acting antipsychotic discontinuation rates under ordinary clinical circumstances: a survival analysis from an observational, pragmatic study. CNS Drugs 2021; 35: 655–665.

48.

Stevens

Dawson

Zummo

Clinical benefits and impact of early use of long-acting injectable antipsychotics for schizophrenia. Early Interv Psychiatry 2016; 10: 365–377.

49.

Ifteni

Petric

P-S

Teodorescu

Rating Opportunity for Long-Acting Injectable Antipsychotic Initiation Index (ROLIN). Front Psychiatry 2021; 12: 767756.

50.

Marcus

Zummo

Pettit

, et al. Antipsychotic adherence and rehospitalization in schizophrenia patients receiving oral versus long-acting injectable antipsychotics following hospital discharge. J Manag Care Spec Pharm 2015; 21: 754–769.

51.

Munday

Greene

Chang

, et al. Early initiation of long-acting injectable antipsychotic treatment is associated with lower hospitalization rates and healthcare costs in patients with schizophrenia: real-world evidence from US claims data. Curr Med Res Opin 2019; 35: 1231–1239.

52.

Kim

Seo

Lee

BC.

Real-world effectiveness of long-acting injections for reducing recurrent hospitalizations in patients with schizophrenia. Ann Gen Psychiatry 2020; 19: 1.

53.

Magliocco

de Filippis

Aloi

, et al. Second-generation long-acting injections anti-psychotics improve executive functions in patients with schizophrenia: a 12-month real-world study. Int J Psychiatry Clin Pract 2020; 24: 201–207.

54.

Tiihonen

Walhbeck

Lönnqvist

, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 2006; 333: 224.

55.

Takács

Kunovszki

Timtschenko

, et al. Comparative effectiveness of second generation long-acting injectable antipsychotics based on nationwide database research in Hungary: an update. Schizophr Bull Open; 3. Epub ahead of print 1 January 2022. DOI: 10.1093/schizbullopen/sgac013.

56.

Brasso

Bellino

Bozzatello

, et al. Second generation long-acting injectable antipsychotics in schizophrenia: the patient’s subjective quality of life, well-being, and satisfaction. J Clin Med 2023; 12: 6985.

57.

Tiihonen

Taipale

Mehtälä

, et al. Association of Antipsychotic polypharmacy vs monotherapy with psychiatric rehospitalization among adults with schizophrenia. JAMA Psychiatry 2019; 76: 499.

58.

Correll

Rummel-Kluge

Corves

, et al. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull 2009; 35: 443–457.

59.

Tiihonen

Mittendorfer-Rutz

Majak

, et al. Real-world effectiveness of antipsychotic treatments in a nationwide cohort of 29 823 patients with schizophrenia. JAMA Psychiatry 2017; 74: 686.

60.

Hamina

Taipale

Lieslehto

, et al. Comparative effectiveness of antipsychotics in patients with schizophrenia spectrum disorder. JAMA Netw Open 2024; 7: e2438358.

61.

Kishimoto

Hagi

Nitta

, et al. Effectiveness of long-acting injectable vs oral antipsychotics in patients with schizophrenia: a meta-analysis of prospective and retrospective cohort studies. Schizophr Bull 2018; 44: 603–619.

62.

Rubio

Schoretsanitis

John

, et al. Psychosis relapse during treatment with long-acting injectable antipsychotics in individuals with schizophrenia-spectrum disorders: an individual participant data meta-analysis. Lancet Psychiatry 2020; 7: 749–761.

63.

García-Carmona

García-Pérez

Isidro García

, et al. Preliminary data from a 4-year mirror-image and multicentre study of patients initiating paliperidone palmitate 6-monthly long-acting injectable antipsychotic: the Paliperidone 2 per Year study. Ther Adv Psychopharmacol. Epub ahead of print 26 January 2023. DOI: 10.1177/20451253231220907.

64.

Calvin

Minischetti

Salanon

, et al. Combination of two long-acting injectable antipsychotics in treatment-resistant schizophrenia: a retrospective 12-month mirror-image study. Asian J Psychiatr 2023; 80: 103402.

65.

Montemagni

Del Favero

Cocuzza

, et al. Effect of long-acting injectable antipsychotics on hospitalizations and global functioning in schizophrenia: a naturalistic mirror-image study. Ther Adv Psychopharmacol. Epub ahead of print 8 January 2022. DOI: 10.1177/20451253221122526.

66.

Bedggood

Walton

Psychiatric hospitalisation before and after commencing long-acting injectable antipsychotic medication: a mirror-image study. N Z Med J 2022; 135: 37–47.

67.

Gentile

Discontinuation rates during long-term, second-generation antipsychotic long-acting injection treatment: a systematic review. Psychiatry Clin Neurosci. Epub ahead of print 27 January 2019. DOI: 10.1111/pcn.12824.

68.

Tatini

D’Anna

Pietrini

, et al. Predictors of long-acting injectable antipsychotic treatment discontinuation in outpatients with schizophrenia: relevance of the Drug Attitude Inventory-10. Int Clin Psychopharmacol 2021; 36: 181–187.

69.

Aguglia

Fusar-Poli

Natale

, et al. Factors associated with medication adherence to long-acting injectable antipsychotics: results from the STAR network depot study. Pharmacopsychiatry 2022; 55: 281–289.

70.

Lian

Kim

Procyshyn

, et al. Efficacy of long-acting injectable versus oral antipsychotic drugs in early psychosis: a systematic review and meta-analysis. Early Interv Psychiatry 2021; 16: 589–599.

71.

Winter-van Rossum

Weiser

Galderisi

, et al. Efficacy of oral versus long-acting antipsychotic treatment in patients with early-phase schizophrenia in Europe and Israel: a large-scale, open-label, randomised trial (EULAST). Lancet Psychiatry 2023; 10: 197–208.

72.

Schneider-Thoma

Chalkou

Dörries

, et al. Comparative efficacy and tolerability of 32 oral and long-acting injectable antipsychotics for the maintenance treatment of adults with schizophrenia: a systematic review and network meta-analysis. Lancet 2022; 399: 824–836.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.04 MB

0.02 MB

Impact of treatment with long‑acting injectable antipsychotics on hospitalization and relapse rates in schizophrenia spectrum disorders: a 3‑year follow-up mirror‑image study

Abstract

Background:

Objectives:

Methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Study design

Measures

Statistical analysis

Results

Study participants

Hospitalization rates: Mirror‑image analyses

Relapse rates: Mirror‑image analyses

Hospitalization days and relapse rates before and after LAI initiation: Mirror‑image analyses

Discussion

Limitations

Conclusion

Supplemental Material

sj-docx-1-tpp-10.1177_20451253251403263 – Supplemental material for Impact of treatment with long-acting injectable antipsychotics on hospitalization and relapse rates in schizophrenia spectrum disorders: a 3-year follow-up mirror-image study

Supplemental Material

sj-docx-2-tpp-10.1177_20451253251403263 – Supplemental material for Impact of treatment with long-acting injectable antipsychotics on hospitalization and relapse rates in schizophrenia spectrum disorders: a 3-year follow-up mirror-image study

Footnotes

Acknowledgements

Declarations

Ethics approval and consent to participate

Consent for publication

Author contributions

Funding

Competing interests

Availability of data and materials

ORCID iDs

Supplemental material

References

Supplementary Material