Schizophrenia is a severe mental disorder that affects approximately 24 millions of patients worldwide (1). It is characterized by a wide range of symptoms, including cognitive, affective and sensorimotor disturbances alongside positive and negative psychotic symptoms (2). Schizophrenia is associated with broad impairments in cognition, significantly impacting functional recovery and quality of life as well as with higher rates of comorbid mental health disorders such as substance misuse (3). Despite extensive research efforts, the underlying biological and genetic causes of schizophrenia remain poorly understood (4). Dysregulation of neurotransmitters appears to play a crucial role in the pathophysiology of schizophrenia. While dopamine dysregulation has long been a central focus in understanding the disorder, recent evidence suggests that abnormalities in other neurotransmitter systems, such as serotonin, glutamate, gamma-aminobutyric acid (GABA), and acetylcholine, also contribute significantly to the development and progression of the disease (5). Nevertheless, past and current antipsychotic treatments are designed to target and modulate the dopaminergic system.

Long-acting injectable (LAI) antipsychotics represent a significant advancement in the treatment of schizophrenia, particularly but not exclusively, for patients who struggle with medication adherence (6). A recent systematic review found that second-generation antipsychotics (SGAs) were generally associated with improvements in quality of life compared to first-generation antipsychotics (FGAs) (7). The review noted that factors such as side effects, adherence, and personal preferences significantly influence the overall benefits of antipsychotic treatment. Furthermore, the use of long-acting injectable antipsychotics was associated with a stable improvement in the levels of quality of life (7). This effect should be due to the several pharmacokinetic advantages introduced by LAI drugs, which allow for a more stable blood concentration of the drug, with lower rates of side-effects and a better long-term compliance with the treatment. (7, 8).

Paliperidone palmitate six-monthly (PP6M) LAI allows for six-monthly dosing, providing the longest dosing interval, among all currently available LAIs. To date, clinical trials demonstrated that PP6M is non inferior compared to PP3M in preventing relapse in patients with schizophrenia adequately treated with PP1M or PP3M in Western and Asian countries (9, 10). A recent study compared PP6M treatment outcomes between the patients included in the above mentioned clinical trial with a real-world external comparator arm (patients treated with PP1M and PP3M) in the US (11) and showed higher PP6M efficacy in reducing and delaying relapses and improved long-term symptom control compared to PP1M/PP3M in usual-care settings (11). To the best of our knowledge, thus far there is only one published study evaluating the role of PP6M in real world practice. Preliminary findings in patients with a wide variety of diagnoses showed a 94% adherence rate for PP6M at 6 months (12). In this regard real world studies, in particular mirror-image studies, offer several advantages, particularly in evaluating treatment efficacy. By comparing the patient’s condition before and after treatment, these studies control for individual differences, making them a powerful tool for assessing the impact of an intervention. This design minimizes confounding variables, as each patient serves as their own control (13). In the present study we aimed to evaluate the long-term real-world effectiveness, adherence and safety of PP6M in patients with a diagnosis of schizophrenia.

The study is conducted in accordance with International Conference on Harmonization Good.

Clinical Practice guidelines, the Declaration of Helsinki and approved by the corresponding Ethics Committee (ref. CEI.23-11_PY2_2022). The protocol and consent forms were approved by the respective institutional ethics committee at each site.

Data derived from the cohort of patients enrolled in the international, multicenter and prospective mirror-image Paliperidone-2-per Year (P2Y) study. The study protocol was previously published elsewhere (12). Here, we designed a 2-year mirror-image study ( Figure 1 ) to determine the effectiveness of PP6M compared to the previous treatment in patients diagnosed with schizophrenia. Adults carrying a diagnosis of schizophrenia, schizoaffective, psychotic, delusional, bipolar or personality disorders, intellectual disability and autism spectrum disorders initiating PP6M treatment were included. Patients <18, pregnant women and those without medical records in the past 2 years were excluded. Data collected extend from 2021 to 2024 and included both outpatients and long-stay inpatients or those in residential care. The index date of the study was defined as the point at which the first dose of PP6M was administered; information was subsequently collected for one year prospectively and one year retrospectively to determine clinical outcomes. Treatment was not predetermined so clinical decisions were taken by the psychiatrists and their patients. There were no exclusion criteria regarding comorbid substance use or affective disorders or other concomitant pharmacological treatments.

Here, we present data on patients characteristics, effectiveness and adherence to PP6M compared with the previous treatment up to 1 year after the switch in a naturalistic cohort of patients diagnosed with schizophrenia. A total of 201 patients (107 outpatients and 94 inpatients living in a chronic mental health hospital or residential care home) were recruited as part of the P2Y study and included in this analysis. Sociodemographic and clinical characteristics are outlined in Table 1 and include the total cohort as well as the two sub-groups separately so as to avoid biases and capture potential differences. To this end, it is worth noting that the outpatients subgroup were significantly younger (48.1 ± 1.3 vs. 55.3 ± 1.0, p=0.001), composed by a wide variety of races (p=0.001) in contrast to the long-stay chronic patients that were older and mostly Caucasian (97%). Furthermore, 17% of outpatients were employed compared to only 1% in the chronic inpatient subgroup (p=0.001). 55% of patients in the total cohort smoked tobacco and used other substances without differences between subgroups. Nonetheless, a significantly higher prevalence of tobacco (p=0.016) or cannabis (p=0.041) smokers were found in the inpatients and the outpatients subgroups, respectively. 15% of patients carried a recorded comorbid diagnosis of SUD again without any differences between subgroups. 19% of patients were previously treated with PP1M, 76% switched from PP3M, 3% from aripiprazole 1-monthly (A1M), 2% from other LAIs [risperidone-LAI (RLAI) or zuclopenthixol-LAI (ZLAI)] and 3% from oral antipsychotics. No differences were found in the previous treatment of the patients between subgroups though a statistical trend was noted in the proportion of patients treated previously with PP3M (86% inpatients vs. 66% outpatients, p=0.071). The dosage of previous treatments and the reasons for switching to PP6M are summarized in Table 1 . Higher doses of PP3M were used in the inpatients (620 ± 32mg) compared to the outpatients subgroup (534 ± 28mg, p=0.038). No other dosage differences were found. Among the reasons for switching to PP6M, 39% of patients and 51% of clinicians preferred treatment with PP6M and only 2% reported side effects, 3% no adherence and 4% ineffectiveness of the previous treatment.

The P2Y observational, 4-year mirror-image study is being conducted at multiple sites in Europe in order to capture the wider clinical use and application of PP6M. Here, we present real world data about the use of PP6M in clinical practice including treatment discontinuation and its reasons for the first 201 patients diagnosed with schizophrenia and initiated on PP6M across multiple European settings. To our knowledge, this is the first mirror image study of PP6M with a 1-year follow-up period. In contrast with previous clinical trials (9) carried out with PP6M in patients diagnosed with schizophrenia here we included patients with a variety of comorbidities including substance misuse, and physical comorbidities, such as metabolic syndrome and cardiovascular disease as well as patients with concomitant use of mood stabilizers or antidepressants and other antipsychotics to better reflect pragmatic clinical conditions.

The overall compliance of 94% with PP6M was remarkable in this naturalistic cohort 1 year after treatment initiation. In fact, 90.4% of outpatients and 97.8% of inpatients in our cohort received the third PP6M administration. In the post hoc analysis of two clinical trials in European and Asian cohorts, authors compared discontinuation between a group of patients treated with PP6M and PP3M during 1 year and found a similar retention rate (89% and 87%) for PP6M after 12 months treatment in outpatient settings (10, 15). Therefore, our results are overall in agreement with data from clinical trials demonstrating high rates of PP6M compliance in European settings after 1 year or slightly more favorable particularly for the chronic inpatient group. Furthermore, the treatment persistence appears to be much more favorable compared to PP1M; for example an independent study evaluating the long-term real world effectiveness and acceptance of PP1M, reported that 79.5% of patients with schizophrenia continued treatment at one year post-PP1M initiation (16).

Given that most of the patients in our cohort were previously treated with PP3M (and less so with PP1M) for at least 1 year, our findings suggest that adherence in schizophrenia improves when treatment allows for a longer duration of plasma levels and therefore less frequent treatment administrations (17–19). Moreover, there is a growing body of evidence suggesting that even after discontinuing medication, there is a lower risk of relapse in long-acting antipsychotic treatment compared to oral treatment (20, 21). In this regard, further studies are needed to establish the role of PP6M compared to oral and other LAIs antipsychotics.

Furthermore, only 1 (0.5%) patient reported adverse effects (i.e. extrapyramidal side effects) as the reason to discontinue PP6M treatment. Similarly, in a previous clinical trial only 1% of patients reported side effects as the reason to withdraw from treatment (15). 5 outpatients (4.6%) were non-adherent to PP6M and missed more than 4 weeks of the scheduled administration.

Previous data derived from open-label extension clinical trials showed that 121 patients treated with PP-6M remained clinically stable as evidenced by PANSS and CGI-S scores over the 2-year follow-up period (22). In contrast, our results showed a significant decrease in CGI-s score after 1 year of PP6M treatment. Strikingly, this reduction in the CGI-s was more pronounced in the long-stay subgroup. This difference may be explained by several factors such as 1) greater subjective improvement component since the patients in our cohort are more heterogeneous than in clinical trials, 2) shorter follow-up period in our study and 3) better compliance in our sample. Nonetheless, further studies specifically designed are needed to evaluate the potential clinical improvement with PP6M compared to other LAIs.

The aforementioned clinical trials also evaluated the number of relapses in patients diagnosed with schizophrenia and treated with PP6M though did not separately record on the number of psychiatric hospital admissions. Relapse in these studies was defined and measured as time to first occurrence of at least 1 of the following events: psychiatric hospital admission, emergency room visits for worsening symptoms, suicide attempt or injury to another person or significant property damage. Nonetheless, a recent study derived from a clinical trial reported that 2.2% of patients were admitted during the 2-year follow-up period (23). In this regard, 2.9% of the patients in our cohort were admitted during 1 year of follow-up and given the real world conditions of our study, a slightly higher percentage of admissions should be expected in our cohort after 2 years. In clinical trials PP6M demonstrated to be non-inferior compared to PP3M and ensured the maintenance of clinical efficacy in the long term. It is noteworthy however, that our results demonstrated that PP6M reduced hospital admissions compared to the previous antipsychotic treatment, mainly PP3M, in those patients who were previously admitted.

Last, it could be encouraging to confirm in future studies with PP6M some of the clinical effects demonstrated with its predecessors. In this regard, PP1M significantly improved non-core symptoms, which include negative symptoms and cognitive impairments, thereby suggesting that PP6M could have a broader therapeutic benefit that extends beyond symptom management to impact overall quality of life (QoL) (24). This ties into the findings of Sampogna et al. (7), who highlighted the positive effects of second-generation antipsychotic treatment, in particular LAIs, on QoL in patients with schizophrenia. Further strengthening the case for PP6M, Besana et al. (25) highlighted that LAIs may play a significant role in reducing the risk of readmission in first-episode psychosis patients. The study found that those receiving LAI treatment had lower rates of rehospitalization compared to patients on oral medications, emphasizing the potential for these medications to influence the long-term trajectory of early psychosis. In practical terms, reduced readmissions, fewer relapses, and better adherence with PP6M would likely lead to lower hospitalization rates, which are a significant economic burden in schizophrenia management (1). Furthermore, by improving QoL and functional outcomes, PP6M may reduce the need for extensive social support and long-term care, which could help optimize healthcare resource utilization. Therefore, future studies are needed to evaluate this possible additional benefit of PP6M compared to other LAIs in preventing hospital admissions, relapses and its impact on the quality of life of patients.

Several limitations of our study need to be considered. First, although the number of subjects included in this study (n = 201) was relatively large, the size may still be insufficient to fully represent the entire population of patients with schizophrenia. Second, since we only included data collected from clinical practice, we were unable to assess specific symptom scale scores, making it challenging to determine the precise changes in symptoms. Third, while using a mirror-image study design may ensure that some patient specific variables can be controlled and remain constant, it cannot account for other important factors such as changes in socioeconomic variables, patients age or differences in prescribing practices among different regions or individual practice among clinicians, including the shared and supported decision making process. Forth, selection bias was minimized by including a consecutive sample of eligible patients prescribed PP6M at the discretion of clinicians in the absence of any restrictive or prescriptive practice.

This is the first mirror-image study in patients with schizophrenia treated with PP6M in both real-world settings, out- and in-patients, showing high treatment persistence and no major safety concerns, as well as reduced hospital admissions compared with previous antipsychotic treatments, mainly PP-3M LAI. Our findings suggest that six-monthly treatment with PP may have additional benefits compared to previous treatments for patients with schizophrenia and may enhance their quality of life. Further research is needed to assess the long-term impact of PP6M in the patient’s quality of life.