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:

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.

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