Retrospective Analysis of the Effectiveness and Tolerability of Long-Acting Paliperidone Palmitate Antipsychotic in Adolescent First-Episode Schizophrenia Patients

Abstract

Objective:

The aim of this study was to explore the effectiveness and tolerability of long-acting paliperidone palmitate antipsychotic in adolescent first-episode schizophrenia patients while comparing the results with the oral antipsychotic risperidone.

Methods:

This study is a retrospective, noninterventional study to assess the effectiveness and tolerability of long-acting injectable antipsychotic paliperidone palmitate in first-episode adolescent patients during the first 12 months of treatment compared with the oral antipsychotic risperidone. The data include general sociodemographic characteristics, number of hospitalizations, side effects, and the following clinical scales: Positive and Negative Syndrome Scale (PANSS), Personal and Social Performance Scale (PSP), Clinical Global Impression Improvement and Severity (CGI-I and CGI-S), and Treatment Satisfaction Questionnaire for Medication (TSQM).

Results:

During the 12-month study period significant improvement was registered in patients receiving both paliperidone palmitate and risperidone in the following scales: PANSS, PSP, CGI-I, and CGI-S. Patients receiving paliperidone palmitate had significantly greater improvement in PANSS, CGI-S, and PSP compared with the risperidone group. Patients receiving risperidone had significantly higher number of hospitalizations than the patients receiving paliperidone palmitate. The TSQM revealed that the patients who were receiving paliperidone palmitate achieved significantly higher scores on the convenience scale, global satisfaction, and on the overall result, whereas no difference was observed on the effectiveness scale. There were several side effects reported for paliperidone (5.5% hyperprolactinemia, 5.5% weight gain) and risperidone (5.5% hyperprolactinemia, 16.7% weight gain).

Conclusions:

In conclusion, paliperidone palmitate seems to be safe and effective in adolescent patients. Furthermore, it compared favorably with risperidone in the clinical response, side effects, and hospitalizations.

Introduction/Background

Early-onset schizophrenia (EOS) is defined by an onset before 18 years of age and is diagnosed using the same diagnostic criteria as in adults. It is characterized by positive (hallucinations and delusions), negative (apathy, lack of emotional responsivity, and social withdrawal), and cognitive symptoms (deficits in attention, memory and executive functioning) (McClellan et al. 2013). The incidence of schizophrenia is highest in the 20s, but begins to appear in adolescence as well (Kirkbride et al. 2012). EOS often has an insidious onset and is characterized by social withdrawal, academic difficulties, and cognitive delays (Röpcke and Eggers 2005).

The period of adolescence can mask the mentioned symptoms, thus delaying the diagnosis. Unique developmental processes that occur during this period often lead to misdiagnosis as well (Carlson 1990). The hallmark phases of schizophrenia are the prodromal, acute, recovery, and residual phase. The course of the disease is the same as in adults, although with a subtler prodrome and a worse long-term outcome (Immonen et al. 2017). Antipsychotic treatment in EOS is generally efficacious, although with more severe side effects and reduced treatment response (Mattai et al. 2010).

Antipsychotics have been a cornerstone in treating psychosis since their introduction during the last century. They are classified into three generations, each having different pharmacodynamic, pharmacokinetic, and side effects. Although all are considered effective in treating psychosis by acting on the dopamine receptors, all generations of antipsychotics have significant side effects. Extrapyramidal side effects (tardive dyskinesia) are present in all generation of antipsychotics (D'Abreu et al. 2018), whereas metabolic side effects (weight gain, diabetes, and metabolic syndrome) are more prevalent in second- and third-generation antipsychotics (Tschoner et al. 2007).

The mentioned side effects are present in both oral and long-acting injectable (LAI) formulations of antipsychotics and can be significant; therefore constant monitoring for side-effect appearance and a careful risk–benefit assessment are warranted when administering antipsychotics (Vancampfort et al. 2015). Although the medications are effective, patient adherence and subsequent relapse remains an issue (Emsley et al. 2013). One of the possible solutions to this issue is changing the way the drug is administered. Adult patients who receive LAI solutions have better adherence and lower relapse rates while maintaining similar or higher efficiency achieved by oral administration (Chue and Emsley 2007). However, any possible difference in effectiveness between LAI antipsychotics and oral antipsychotics is a debated topic, mostly because of the difficulties in creating truly randomized studies (Kane et al. 2013). The lack of studies is even more pronounced in adolescents.

There is a growing body of evidence that antipsychotics are effective and tolerable for adolescents suffering a first episode of schizophrenia (Castro-Fornieles et al. 2008; James 2010; Sarkar and Grover 2013). Most of the studies focus on oral antipsychotics as they are used as a first-line treatment in EOS. The issue of adherence is especially pronounced within adolescents because of the significant physical, emotional, social, sexual change, and maturation that occur during development (Taddeo et al. 2008). Adolescents often forget to take their medications or stop altogether, leading them to relapse and further deterioration (Emsley et al. 2013).

LAI antipsychotics can be a possible solution to these problems, treating their condition effectively and preventing rehospitalization and relapse while improving the quality of life (Kishimoto et al. 2018). The problem is the lack of studies and approved drugs focusing on this type of treatment in adolescents, although the studies that are available show potentially similar effectiveness and tolerability as in adults (Ruan et al. 2010; Boarati et al. 2013; Fàbrega et al. 2015).

The aim of this study was to retrospectively assess the effectiveness and tolerability of long-acting injectable paliperidone palmitate (LAIPP) in first-episode adolescent patients, while comparing the results with the oral antipsychotic risperidone.

Methods

Study design

This study is a retrospective, noninterventional study to evaluate the effectiveness and tolerability of LAIPP in first-episode adolescent patients during the first 12 months of treatment compared with the oral antipsychotic risperidone. Oral antipsychotic risperidone was chosen for comparison because of its pharmacological relationship to paliperidone as oral paliperidone is not approved for use in Croatia. The study timeframe for the medical records search was from 2014 to 2017, with 18 suitable patients found for both groups. The diagnosis of schizophrenia was made with patient history, clinical course, and the diagnostic criteria laid out by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).

The patients were drug-naive before treatment. The start date for the retrospective documentation was the first injection date (baseline—after a 2-week stabilization on risperidone), whereas the end period was after the first 12 months of continuous treatment of LAIPP. The risperidone group start date for retrospective analysis was after the stabilization period of initial symptoms, comparable with the 2-week stabilization period for the paliperidone palmitate group. Patients from both groups regularly attended control visits to the outpatient clinic throughout the duration of the study. The outpatient control visits for patients with EOS in our clinic are once per month or more often if needed. The once-monthly control visits include monitoring of therapy effectiveness and administering of clinical scales. As per standard clinical protocol in our center, the patients and their guardians chose whether they would like the oral or injectable antipsychotics to start their treatment.

Appearance of side effects was monitored on every control visit; of the two reported side effects hyperprolactinemia was defined as elevated serum prolactin without galactorrhea or amenorrhea, whereas weight gain was defined as an increase of ≥7% body weight during a period of 3 months during the course of the study, attributable to the medication and not a change in lifestyle. Cannabis use was assessed at baseline, and was ceased for all patients after start of treatment. The patients were tested for cannabis use by urine drug screening every 4 months.

Retrospective data are available from the integrated electronic hospital medical documentation system at the Department of Child and Adolescent Psychiatry, Clinical Hospital Centre Rijeka, a tertiary medical center covering a population of ∼400,000 people. The data include general sociodemographic characteristics described further in text, number of hospitalizations, side effects, and clinical scales for measuring treatment effectiveness and satisfaction with treatment [Positive and Negative Syndrome Scale, (PANSS) (Kay et al. 1987), Personal and Social Performance Scale, PSP (Morosini et al. 2000), Clinical Global Impression Improvement and Severity, CGI-I and CGI-S (Busner and Targum 2007), Treatment Satisfaction Questionnaire for Medication, TSQM (Atkinson et al. 2004)].

The TSQM was designed to assess patient treatment satisfaction in chronic diseases and has been validated extensively since its inception (Bharmal et al. 2009). It consists of 4 (effectiveness, convenience, global satisfaction, and side effects) scales divided into 14 items. The data for the TSQM were obtained twice, 6 months after start of treatment and at the end of the first year of treatment, as per standard clinical protocol in our clinical center. All scales were performed by two trained psychiatrists, with the same psychiatrist per patient during treatment. PANSS, PSP, CGI-I, and CGI-S were performed once a month on each control visit, whereas TSQM was obtained every 6 months.

The inclusion criteria for the study were the following: patients' age (<18 years old, no minimum age), documented diagnosis of schizophrenia according to the DSM-IV (Guze 1995), first psychotic episode, a signed informed consent, and assent for data collection and publication by the patients, parents, or legal guardians. The exclusion criteria for the study were the following: a DSM-IV psychotic disorder diagnosis other than schizophrenia, any previous treatment for the disease other than the oral antipsychotic risperidone, incomplete records for the 12-month period of treatment, and irregular control visits.

Statistical analysis

Demographic and baseline characteristics were summarized using descriptive statistics and groups were compared using t-test or χ ² test. Changes in PANSS and PSP were analyzed using repeated-measures analysis of variance with the type of medication as a between-subject factor. Changes in ordinal measures: CGI-S and CGI-I were analyzed using Friedman's test and Mann–Whitney U-test. Differences in treatment satisfaction were examined using t-test. Level of statistical significance was set to p < 0.05. Data were analyzed using the IBM SPSS statistical package, version 16.

Results

Sociodemographic characteristics

A total of 197 patient records were analyzed from the study timeframe (2014–2017), of which a total of 36 patient records were suitable for analysis per the aforementioned inclusion and exclusion criteria. The age range of patients analyzed was from 15 to 18 years of age. Among the 36 analyzed patients, 18 received LAIPP and 18 received risperidone. In general, the demographic and baseline characteristics (mean age, sex, divorced parents, close relatives with psychotic disorders, and cannabis use) were similar among the treatment groups (Table 1).

Table 1.

Differences in Sociodemographic Characteristics of Patients Receiving Long-Acting Injectable Paliperidone Palmitate and Risperidone

	Paliperidone palmitate, n = 18	Risperidone, n = 18	t/χ²	p
Age, years, mean (SD)	16.56 (0.62)	16.17 (0.86)	1.56	0.127
Sex, male, n (%)	10 (55.6)	9 (50.0)	0.11	0.738
Dysfunctional family, yes, n (%)	12 (66.7)	11 (61.1)	0.12	0.729
Close relatives with psychotic disorders, yes n (%)	8 (44.4)	13 (72.2)	2.86	0.091
Cannabis, yes n (%)	5 (27.8)	4 (22.2)	0.15	0.700
Anxiety disorder, yes, n (%)	3 (16.6)	4 (22.2)	0.13	0.722

SD, standard deviation.

A high percentage of patients had dysfunctional families in both analyzed groups (66.7% LAIPP; 61.1% risperidone), which we defined as families where parents or guardians were divorced, had mental illness, or substance abuse present in parents or guardians. In these families there was a lack of support toward the patient. A large proportion of patients also had close relatives with psychotic disorders, indicating a certain predisposition toward mental illness. There were no significant differences between the two groups in this category. Cannabis use at baseline was positive for 27.8% of patients in the LAIPP group and 22.2% of patients in the risperidone group; however, cannabis use was ceased after baseline. Finally, the only comorbidity diagnosed in these patients was anxiety disorder, which was present in 16.6% of patients on LAIPP and 22.2% of patients in the risperidone group.

Dosage

Dosage of both medications was adjusted as a result of response in clinical scales, clinical impression, and side effects of the patients, whereas LAIPP dosage was also adjusted due to titration guidelines. During treatment 77% (n = 28) of patients were also prescribed anxiolytics according to clinical indications at the beginning of treatment, whereas 19.4% (n = 7) of patients had anxiolytics prescribed during the duration of the study to be taken as needed.

Long-acting injectable paliperidone palmitate

At baseline 13 (72.2%) patients received 150 mg and the other 5 (27.8%) patients received 100 mg as the initial dose. At the first month, 2 (11.1%) patients received 150 mg, 9 (50%) patients received 100 mg, and 7 (38.9%) patients received 75 mg dose. From month 1 onward, 9 (50%) patients had a dose decrease, 8 (44.4%) did not change their dose, and 1 (5.6%) patient had a dose increase. One year after the initial application of LAIPP, median dose was 75 mg. It is important to note that LAIPP was administered only after the patients were stable on risperidone.

Oral antipsychotic risperidone

The initial dose for all patients receiving the oral antipsychotic risperidone was 1 mg daily. At the first month, 10 (55.6%) patients received 2 mg daily and 8 (44.4%) patients received 3 mg daily. From month 1 onward, 10 (55.6%) patients did not change their dose, 5 (27.8%) patients had a dose increase, and 3 (16.7%) patients had a fluctuating dose (increasing and decreasing in the subsequent measurements). The median dose for the oral antipsychotic risperidone was 3 mg daily 1 year after baseline.

Clinical response

Positive and Negative Syndrome Scale

There was no significant difference in PANSS between groups at baseline. During the 12-month study period symptoms measured by total PANSS score generally decreased in the LAIPP and risperidone [F(13.442) = 196.54; p < 0.001] groups; however, patients receiving LAIPP showed significantly greater reduction in total PANSS symptom score [F(1.34) = 11.78; p < 0.001] compared with the patients receiving risperidone (Fig. 1). Mean (standard deviation [SD]) change from baseline to endpoint in PANSS total scores was −43.89 (8.79) for LAIPP and −35.89 (6.69) for risperidone, which was statistically significant (t = 3.07; p < 0.004) (Fig. 1). Compared with risperidone, patients receiving LAIPP showed significantly greater improvement in PANSS positive symptoms (t = 2.38; p = 0.023) and general psychopathology (t = 2.34; p = 0.025), but not in negative symptoms (t = 1.43; p = 0.163) (Table 2).

FIG. 1.

Changes in PANSS and PSP score during the 12-month study period in patients receiving LAIPP and RP. At baseline there are no significant differences between the groups. There is a significant decrease in PANSS score in both measured groups through the study period, with the LAIPP group having significantly better improvement in symptoms (p < 0.004). The same can be observed with the PSP, with both groups having significantly higher scores from baseline and significant difference between them at endpoint (p < 0.001). LAIPP, long-acting injectable paliperidone palmitate; PANSS, Positive and Negative Syndrome Scale; PSP, Personal and Social Performance Scale; RP, risperidone.

Table 2.

Changes in Functional (Positive and Negative Syndrome Scale and Personal and Social Performance Scale) Scales from Baseline to Endpoint in Both Groups

	Risperidone, n = 18	Paliperidone palmitate, n = 18
PANSS positive subscale, mean ± SD
Baseline	23.1 (2.7)	22.8 (2.4)
Change from baseline to 12th month	−9.9 (2.9)	−12.1 (2.4)
p	—	0.023
PANSS negative subscale, mean ± SD
Baseline	21.6 (2.8)	21 (2.9)
Change from baseline to 12th month	−8.4 (2.6)	−9.7 (2.5)
p	—	0.163
PANSS general psychopathology, mean ± SD
Baseline	46.4 (3.3)	46.3 (5.5)
Change from baseline to 12th month	−19.9 (7.6)	−22.2 (5.9)
p	—	0.025
PANSS total score, mean ± SD
Baseline	89.9 (9.5)	90.9 (7.3)
Change from baseline to 12th month	−43.89 (8.79)	−35.89 (6.69)
p	—	0.004
CGI-S, median (range)
Baseline	5 (4.6)	5 (4.6)
Change from baseline to 12th month	−3 (−4.1)	−3 (−4.2)
p	—	0.018
PSP score, mean ± SD
Baseline	46.4 (6.3)	43.3 (3.3)
Change from baseline to 12th month	29 (4.3)	36.8 (6.1)
p	—	0.001

Bold values indicate significant changes (p ≤ 0.05).

CGI-S, Clinical Global Impression of Severity; CGI-I, Clinical Global Impression of Improvement; PANSS, Positive and Negative Syndrome Scale; PSP, Personal and Social Performance Scale; SD, standard deviation.

CGI-I and CGI-S

During the 12-month study period severity of symptoms measured by CGI-S scale significantly decreased in patients receiving LAIPP [χ ²(13) = 207.99; p < 0.001] and patients receiving risperidone [χ ²(13) = 152.19; p < 0.001]. Similarly, CGI-I scale registered significant improvement both in patients receiving LAIPP [χ ²(12) = 183.68; p < 0.001] and risperidone [χ²(12) = 122.92; p < 0.001]. Median (interquartile range) change from baseline to endpoint in CGI-S scale score was: −3 (2) for LAIPP and −2.5 (2) for risperidone. Median (interquartile range) change from week 1 to endpoint in CGI-I scale was 2 (0) for both LAIPP and risperidone (Table 2).

At the baseline assessment, there was no statistical difference in CGI-S scale between patients receiving LAIPP and patients taking risperidone (Mann–Whitney U = 331.5; p = 0.995). At the final assessment patients receiving LAIPP showed significantly lower results on CGI-S scale compared with patients taking oral antipsychotic (Mann–Whitney U = 247.5; p < 0.001).

Personal and social functioning

There was no significant difference in PSP between groups at baseline. During the 12-month study period patient functioning measured by PSP improved significantly from baseline to endpoint both in patients receiving LAIPP and risperidone [F(5.165) = 176.05; p < 0.001]; however, patients receiving LAIPP showed significantly greater improvement in personal and social functioning [F(1.34) = 58.31; p < 0.001] compared with patients receiving risperidone (Fig. 1). Mean (SD) change from baseline to endpoint in PSP total scores was 36.83 (6.09) for LAIPP and 29.0 (4.31) for risperidone, with the difference being statistically significant (t = 4.45; p < 0.001) (Table 2).

Hospitalizations

Hospitalizations at baseline included 5 (27.8%) patients receiving LAIPP and 6 (33.3%) receiving risperidone. During the 12-month study period, 2 (11.1%) patients receiving LAIPP and 9 (50.0%) patients receiving risperidone were hospitalized, which is a statistically significant difference (χ ² = 6.42; p = 0.027). At the same time, 8 (44.4%) patients receiving risperidone were hospitalized once and 1 (5.6%) patient was hospitalized twice. Both patients (11.1%) receiving LAIPP were hospitalized only once.

Treatment satisfaction and side effects

Patients who were taking LAIPP compared with those who took risperidone achieved significantly higher scores on the convenience scale, global satisfaction, and on the overall result, whereas no difference was observed on the effectiveness scale in the TSQM (Table 3).

Table 3.

Scores on Treatment Satisfaction Questionnaire for Medication Domains in the End of 12-Month Study Period in Patients Receiving Long-Acting Paliperidone Palmitate and Risperidone

Mean (SD)	Paliperidone palmitate, n = 18	Risperidone, n = 18	t	P
Effectiveness	12.44 (1.42)	11.44 (1.85)	1.82	0.087
Convenience	13.77 (1.31)	11.83 (2.64)	2.8	0.010
Global satisfaction	13.94 (0.99)	11.44 (2.01)	4.73	.000
Total	40.17 (2.51)	34.72 (5.64)	3.74	.001

	n = 2	n = 4
Side effects	16.5 (3.11)	10.0 (2.16)	3.43	0.017

SD, standard deviation.

Overall, 2 (12.5%) patients taking LAIPP and 4 (22.2%) patients taking risperidone reported at least one adverse event possibly related to medicament treatment. Reported side effects were hyperprolactinemia and weight gain, of which the latter was significantly higher in patients treated with risperidone (Table 4).

Table 4.

Reported Side Effects During the 12-Month Study Period in Patients Receiving Long-Acting Injectable Paliperidone Palmitate and Oral Antipsychotic

	Paliperidone palmitate, n = 18, n (%)	Risperidone, n = 18, n (%)
Hyperprolactinemia	1 (5.5)	1 (5.5)
Weight gain	1 (5.5)	3 (16.7)

Discussion

The results of our retrospective study show that both risperidone and LAIPP were effective in reducing symptoms and improving personal and social functioning with minimal side effects; however, there are some notable differences between the two. First, LAIPP seems to be more effective than the oral antipsychotic risperidone in reducing the symptoms of the first-episode psychosis in our study, as evidenced by the PANSS scores during the 12-month period. It is important to note that the difference is measured as mean PANSS scores of all patients and is a result of more relapses in the risperidone group. Likewise, personal and social functioning has improved significantly more in patients who were receiving LAIPP than those taking oral risperidone.

Secondly, there was a statistically significant difference in the number of hospitalizations between the two groups, with patients on oral antipsychotics being hospitalized more. Finally, the treatment satisfaction questionnaire revealed that patients on LAIPP expressed higher satisfaction of the therapy, which was shown to be more convenient for them. Both groups felt their therapy was effective, with no statistical difference on effectiveness scale.

There are not many studies covering the effectiveness of LAI antipsychotics in the adolescent population, especially on first-episode schizophrenia patients. Ruan et al. (2010) demonstrated in an open-label study that the LAI antipsychotic formulation of risperidone was safe and effective in the EOS adolescent population, with significant increases in functioning and minimal side effects. Two case reports were reported regarding the effects of LAIPP in adolescents by Fabrega et al. (2015). Both patients were given LAI antipsychotic because of poor compliance and their condition improved after administering the drug with minor side effects.

Furthermore, a case series covering seven adolescents with varied pathologies receiving LAI antipsychotics demonstrated significant improvement using the CGI-I scale. Once again, most the individuals tolerated the medication well (Pope and Zaraa 2016). Lytle et al. (2017) concluded in their recent review that LAI antipsychotic use may improve outcomes and adherence, along with a comparable side-effect profile to oral antipsychotics.

The most recent observational study by Fortea et al. (2018) also confirms the effectiveness and tolerability of second-generation LAI antipsychotics in adolescents comparable with the results in this study, although like others, it is limited by a small sample size. All mentioned studies indicate that the LAI antipsychotics were effective and safe, which is in line with our study as well.

There are far more studies covering LAI antipsychotics in adults, with a wide range of drugs available. Kishimoto et al. (2018) concluded in a meta-analysis that LAI antipsychotics demonstrate strong superiority over oral antipsychotics in preventing hospitalizations, which was seen in our study as well. Risperidone group rehospitalization rates are higher than those found in literature (Chan et al. 2015); however, that could be caused by the age-specific differences because of the generally worse adherence in adolescent populations (Taddeo et al. 2008).

Furthermore, an open-label randomized study by Schreiner et al. (2015) compared LAIPP and oral antipsychotics, concluding that LAIPP was superior in relapse prevention and that the patients receiving LAIPP had lower PANSS scores at endpoint. These findings are comparable with those demonstrated in our study, especially regarding PANSS score. Likewise, other studies showed similar effectiveness and tolerability of LAI antipsychotics in adult populations, whereas improvements over oral antipsychotics can mostly be seen in patient adherence and reduced relapse rates (Parellada et al. 2005; Fu et al. 2013). Furthermore, the effectiveness and tolerability of risperidone was adequate as well in most patients.

The results in this study are comparable with other larger studies in the field, which point out the general effectiveness of risperidone, with similar side effects (Zalsman et al. 2003; Pandina et al. 2012). Naturally, there are some risks and drawbacks to using LAI antipsychotics in treating patients. Mainly it is the slow dose titration and the longer time needed to reach steady-state levels, which creates a need for oral antipsychotic supplementation in acutely ill patients (Agid et al. 2010). Another possible risk is the prolonged duration of severe side effects, because of the fixed monthly dose. This also brings the issue of less flexibility in dose adjustments in the short-term periods. Furthermore, administration requires training of the medical staff as improper use can cause pain, along with irritations and lesions of the subcutaneous tissue or skin (Brissos et al. 2014).

Effectiveness and tolerability are not the only factors influencing the success of treatment in schizophrenia patients, as patient satisfaction with treatment plays an important role in adherence to treatment (Bharmal et al. 2009). We monitored patient satisfaction using the TSQM scale, with LAIPP group having a significantly higher score in the overall results compared with the risperidone group. This is in line with recent studies that also point out a greater patient satisfaction with LAI antipsychotics, along with a significantly higher satisfaction of the hospital staff as well (Lloyd et al. 2010). Of importance, a more positive subjective experience of the treatment can indicate a better quality of life in general, and it can lead to better outcomes and stronger adherence (Fujikawa et al. 2008; Kaplan et al. 2013).

Although LAI antipsychotics are seemingly effective in all populations, a growing number of studies find that the strongest benefits are when used in first-episode schizophrenia patients. As mentioned before, there is evidence that LAI antipsychotics are superior to oral antipsychotics with regard to adherence and prevention of relapse; however, several studies point out the increased effectiveness of the medication as well in first-episode patients (Emsley et al. 2008; Kim et al. 2008). Our results are similar to those found in these studies, although the overall discrepancy in effectiveness can be attributed to poor adherence and increased hospitalizations in patients taking risperidone.

Furthermore, the diagnosis of EOS is often a challenge in the clinical settings. The diagnosis is made according to the DSM-IV, which requires two of the following symptoms present for a significant time period during 1 month: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms (affective flattening, alogia, or avolition). Active psychotic symptoms need to be present for at least 1 month and the total duration of illness must be at least 6 months (Guze 1995).

However, although the criteria seem straightforward, the difficulty comes from the specific differences between adolescents and adults. Problems similar to the prodromal phase of schizophrenia such as social withdrawal, difficulty concentrating, bad grades, or abuse of substances occur in adolescents who do not have schizophrenia, thus leading to misdiagnosis or a delay in diagnosis of the disease. Furthermore, adolescents often present with symptoms characteristic for other psychiatric disorders, such as depression and anxiety disorders (Cheng and Mcclellan 2004). Overall, this causes difficulties in finalizing the diagnosis and presents a limitation for this study as well, because it is difficult to have adequate conditions for clinical studies covering this population and disease.

This study has several limitations. Primarily, the sample size is small, which limits confidence in the results. The study is retrospective and not blinded, which opens the possibility for more bias as compared with prospective, blinded, and controlled studies. Furthermore, there were no objective or subjective measurements of adherence in the risperidone group other than the increased number of hospitalization and relapse. Naturally, the patients receiving LAIPP had full compliance because of the injections taking place with supervision at the clinic. However, taking the limitations in mind, there is a small amount of studies covering this population and types of medication, which we believe there is a need of.

Conclusions

Treating schizophrenia in adolescent patients is an arduous task, as there is a severe lack of options available to physicians. Most of the medications are not approved for this population because of a lack of extensive studies. Although our study is limited by the small sample size and the fact that it is not a randomized controlled study, it does present a small step forward in documenting the effectiveness and tolerability of the sorely needed novel therapies in adolescent patients.

LAI paliperidone palmitate seems to be effective and tolerable in treating first-episode schizophrenia in adolescent patients. Furthermore, it seems to be favorable to risperidone in clinical response, side effects, hospitalization, and treatment satisfaction. Lower hospitalization rate and assured adherence contribute to, arguably, the most important goal in adolescent patients, which is avoiding relapses and preventing further deterioration as much as possible. That is the primary reason why we need to consider LAI antipsychotics as a first-line treatment. However, before it becomes practice, more extensive, randomized controlled studies are needed, not only in adolescents but in all populations suffering from schizophrenia, as well as studies with a longer timeframe.

Clinical Significance

The number of studies covering the topic of LAI antipsychotics in adolescents and first-episode schizophrenia patients is limited. A major goal in patients with schizophrenia is avoiding the rehospitalization, relapses, and preventing further deterioration, which is often caused by poor adherence, especially in this vulnerable population. Administering LAI antipsychotics negates the issue of poor adherence, which was evident in this study through a significant reduction of rehospitalizations compared with oral risperidone. In our study paliperidone palmitate seemed to be effective and tolerable in treating first-episode schizophrenia patients, and although the study is not a randomized controlled study, it presents a step toward a possible use of LAI antipsychotics as a first-line treatment for the benefits of our patients.

Footnotes

Disclosures

No competing financial interests exist.

Ethical Standards

This research was approved by the ethics committee of the Clinical Hospital Centre Rijeka and has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Everyone who participated in the study gave their informed consent and assent before inclusion.

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