FormalPara Key Points

There is a lack of randomized clinical trials and a scarce number of studies regarding long-acting injectable antipsychotics (LAIAs) in adolescents with schizophrenia spectrum disorders (SSD). The studies reviewed showed heterogeneous quality and no data was found concerning children < 12 years.

The studies have reported good effectiveness and acceptable tolerability of LAIAs when used to treat adolescents with SSD.

Non-adherence and lack of insight were the main reasons for starting LAIAs in these patients.

Based on the reviewed studies, the authors have made a series of recommendations for use of LAIAs in children and adolescents with SSD.

1 Introduction

Schizophrenia spectrum disorders (SSD) have a high impact on patients, their families and society [1,2,3]. When SSD begin in patients who are under the age of 18 years, they are known as early-onset [4] and their outcome has been reported to be worse than when onset of the disease takes place during adulthood [5]. Early-onset SSD has been linked to severe cognitive deficits [6], social impairment [7], relapses and hospitalizations [1] as well as deterioration in functioning [7] compared with adult-onset SSD.

In the treatment of early-onset SSD, antipsychotics (AP) are key [8]. Different systematic reviews and meta-analyses have confirmed the efficacy of some AP versus placebo in this population [9,10,11]. However, non-adherence to medication is prevalent among adult patients with schizophrenia, reaching rates of over 55% [12]. Risk factors associated with poor adherence include poor insight, negative attitude or subjective response toward medication, a history of previous non-adherence, substance abuse, shorter illness duration, lack of social support, and poorer therapeutic alliance [12, 13]. Adolescent age was described to increase the risk of non-adherence in one systematic review including bipolar disorder and SSD patients [14], but not in another which focused only on patients with SSD [13]. The use of long-acting injectable antipsychotics (LAIAs) is one of the most widely recommended strategies for improving adherence to treatment [15].

LAIAs have been approved as a treatment strategy for schizophrenia in adults, most often used according to patients’ preferences or in order to avoid non-adherence [16, 17]. In adults, the benefits of LAIAs over oral AP have been observed in early psychosis, including first-episode patients [18]. Moreover, there is growing evidence that LAIAs are associated with higher quality of life, improved functional outcomes [19, 20] and reduced risk of relapse and hospitalizations compared with oral AP in adults with schizophrenia [21,22,23,24] and early psychosis [18].

The use of LAIAs in children and adolescents with schizophrenia has been recommended by both the American Academy of Child and Adolescent Psychiatry and the Spanish CIBERSAM guide in cases where there is a personal history of poor adherence to treatment and chronic psychotic symptoms [4, 25]. Nevertheless, LAIAs are not currently approved by regulatory agencies such as the Food and Drug Administration in the United States or the European Medicines Agency in the European Union for use in minors despite the fact that SSD often begin with an onset during childhood or adolescence [26].

Some case reports and mainly retrospective studies have reported on the use of LAIAs in children and adolescents with any psychiatric disorder such as anorexia nervosa, autism or conduct disorder [27,28,29,30,31]. In a literature review published in 2016 [32], of 36 cases involving LAIAs in this population, only seven (19.4%) were minors with schizophrenia, and the rest were diagnosed with bipolar disorder. The authors stated that LAIAs may improve clinical outcomes and adherence in children and adolescents, and found that the side effects were similar to those of oral formulations.

The objective of this systematic review was to summarize findings regarding the effectiveness and side effects of the use of LAIAs in children and adolescents with SSD.

2 Methods

2.1 Literature Search

To perform this systematic review, we followed the 2021 Preferred Reporting Items for Systematic review and Meta-Analyses (PRISMA) guidelines [33]. The systematic review protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the number CRD42022304103.

A systematic literature search was carried out in Web of Science, PubMed, MEDES, and Dialnet databases from inception to March 12, 2022, using the following terms: (antipsychotic OR neuroleptic OR palmitate OR decanoate OR maintena OR pamoate) AND (long acting OR depot OR injectable OR injection) AND (schizophrenia OR psychotic disorder OR psychosis) AND (child OR adolescent OR minor OR youth OR young OR early onset).

2.2 Inclusion Criteria

The criteria for selecting the articles were the following: (1) original articles or case reports; (2) providing data on efficacy/effectiveness or safety/tolerability of LAIA treatment in children and adolescents diagnosed with SSD (schizophrenia, schizoaffective disorder, schizophreniform disorder, non-affective psychotic disorder); (3) mean age of samples ≤ 18 years; and (4) written in English or Spanish.

2.3 Exclusion Criteria

Review articles, clinical guides, expert consensus as well as posters or oral communication in conferences were excluded.

Grey literature as well as clinical trial registers were not searched.

2.4 Data Systematization

The electronic search was conducted in the following steps: first, two researchers (IB and AF) performed the electronic search. Second, both researchers reviewed one by one all of the references from the selected articles using a web platform (www.rayyan.ai) to help with classification. When discrepancies were found, articles were discussed until an agreement was reached. Third, IB and AF extracted the following data from the studies: bibliographic references, place where the study was conducted or the case visited, year of publication, type of study, description of the sample (number, sex, age, diagnoses), type of patient (outpatient/inpatient), type of LAIA, other pharmacological treatment, results of psychiatric assessment (questionnaires, interviews), and outcomes of the study (efficacy/effectiveness, safety/tolerability).

2.5 Quality, Risk of Bias, and Evidence Assessments

The quality of assessment of each study (excluding case reports or case series) was evaluated with the Newcastle-Ottawa scale for case-control or cohort studies [34] with study-specific criteria [35] (Supplemental Table 1, see electronic supplementary material [ESM]).

The risk of bias was assessed for the same studies using the ROBIS tool [36] as is shown in Supplemental Table 2 (see ESM). The evidence of the recommendations was evaluated through the Grading of Recommendations Assessment, Development and Evaluations (GRADE) [37].

3 Results

Out of 847 articles retrieved, 13 articles met eligibility criteria and were reviewed in depth. The flowchart of the reviewed articles and the reasons for exclusion are shown in Fig. 1.

Fig. 1
figure 1

Flow diagram of the article screening process

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The included articles comprised one open-label trial [38], one observational prospective study [39], four retrospective chart review studies [28, 40,41,42], four single case reports [43,44,45,46], and three case series (of 2, 3, and 6 patients with SSD) [47,48,49]. One study included a patient age range of 13–18 years, but the mean age was < 18 years (15.9 ± 3.3) [38]. None of the studies included LAIA use in patients < 12 years. All patients were on second-generation LAIAs, except for one study [40] (which was based on prescription of first-generation LAIAs), one case in a case series [49], and a case series [48] in which patients were on a combination of LAIAs (second-generation and first-generation). In total, 119 patients with SSD were on LAIAs in the included articles. The distribution of patients on the different LAIAs is shown in Fig. 2.

Fig. 2
figure 2

Distribution of long-acting injectable antipsychotic agents in the 119 patients included in the studies reviewed

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3.1 Original Studies

Table 1 describes the main characteristics and results of the six original studies reviewed. The quality of the assessment scale scores for the studies were in the range of 4–9, with a mean and standard deviation of 5.8 ± 1.9. This shows that most of the studies were of low quality.

Table 1 Original studies (N = 6) of children and adolescents on long-acting antipsychotics, listed alphabetically by first author
Full size table

Of the six studies, three (50%) describe the use of LAI risperidone [38, 39, 42]. A 24-week open-label trial in which 31 adolescents with SSD who were clinically stable with oral AP (olanzapine or risperidone) were switched to LAI risperidone reported that the vast majority finished the study (one patient discontinued due to side effects and another for insufficient response) [38]. The use of LAI risperidone (mostly with 25 mg/2 weeks) was associated with improvement in all of the Positive and Negative Syndrome Scale (PANSS) domain scores and was well tolerated. In terms of extrapyramidal symptoms (EPS), one patient (3.2%) with akathisia and two (6.4%) with dystonia were reported, but the most frequent side effects were depression, anxiety, headache, and insomnia.

Ceylan et al. [39] conducted an observational prospective study (with a minimum 2-month follow-up) with hospitalized adolescents who were non-adherent to oral AP. Out of 42 included patients, only two were diagnosed with schizophrenia (one with an intellectual disability comorbidity). All patients were treated with LAI risperidone 25 mg/2 weeks, and a 50% clinical improvement (measured with the Clinical Global Impression [CGI] scale) was found in patients with SSD. Side effects were reported by all patients, and consisted of menstrual problems (39.2% of girls), swollen and tender breasts (28.6%, both sexes), weight gain (23.8%), and somnolence (23.8%). Dystonia was reported in 16.7% and fewer described other EPS such as slowing of movements (14.3%) and restlessness (7.1%). The authors stated that due to the small number of patients with SSD included in the study, it was difficult to draw conclusions about the effectiveness of LAI risperidone in this population.

The other retrospective study focusing on the use of LAI risperidone compared patients with early-onset and adult-onset SSD, finding that the continuation rate of the LAI treatment in early-onset patients was lower than in adult-onset patients, although this difference was not significant [42]. The dose of LAI risperidone was also lower in early-onset patients, although there was no difference in psychopathology severity between the groups. Thus, the authors were unable to find support for the benefits of using LAI risperidone for the treatment of patients with early-onset schizophrenia.

Using LAI paliperidone, Petrić et al. [41] conducted a retrospective study of adolescents with a first-episode of schizophrenia. This study compared patients using LAI paliperidone with others receiving oral risperidone. A total of 27.8% of the patients on LAIA and 22.2% of those on oral AP used cannabis. Although symptoms were associated with improvement with both treatments, total PANSS scores were significantly more reduced in patients on LAI paliperidone after 12 months of treatment, with fewer relapses and hospitalizations. Patients on LAI also showed greater improvement in personal and social functioning, with higher satisfaction with the therapy than patients on oral risperidone.

One study, using a retrospective design, compared adolescent inpatients on LAI risperidone, LAI paliperidone, and LAI aripiprazole, with 73%, 86%, and 58% of each group, respectively, having SSD [28]. Seven (23.3%) of the patients included were in foster care. Comorbid cannabis use was 40%, 86%, and 50% with each type of LAIA, respectively. The sample of patients with cannabis use were older than non-users. All patients were on LAIA due to a history of demonstrated non-adherence or concerns regarding future adherence to oral treatment. Clinical improvement was observed in patients on each LAIA from admission to discharge. Length of hospitalization was shorter in the LAI aripiprazole group compared with LAI risperidone and LAI paliperidone (13 ± 4 vs 20 ± 11 and 22 ± 9 days; p = 0.08), but an effect of differences in diagnoses and severity at admission could not be ruled out. Patients on LAI risperidone had significantly more side effects (45%) than patients on LAI aripiprazole (0%), with hyperprolactinemia being the most frequently reported one.

Finally, one retrospective study was conducted in India with adolescent inpatients with severe mental disorders (including 26 patients with SSD) who received first-generation LAI [40] for different reasons: 65.8% for failed or only partial response to oral AP; 34.2% for severe, aggressive behavior which did not respond to other drugs, and 31.6% for non-adherence with oral AP. They justified the use of first-generation LAIAs due to the cost of the medication. Most of the patients were on LAI fluphenazine (60.5%), but LAI flupentixol (34.2%) and LAI zuclopenthixol (18.4%) were also prescribed. As all of the patients were also on other treatments while on LAIAs, the authors acknowledged that it was difficult to disentangle the role of LAIA in clinical improvement. Side effects were reported in almost 48% of patients, with EPS being the most prevalent one. The authors underscored the value of these LAI formulations in treating severe mental disorders in low and middle-income countries where the cost of treatment plays a significant role that can affect both treatment decisions and adherence.

3.2 Case Reports and Case Series

Pope and Zaraa [49] described nine adolescent inpatients receiving LAIA treatments, six of whom had SSD (two with a cannabis use comorbidity, one with PTSD and one with ADHD). Four (66.7%) of the SSD adolescents were on LAI paliperidone, one (16.7%) on LAI aripiprazole, and one (16.7%) on fluphenazine decanoate. A history of non-adherence was the reason for starting LAIAs in 83.3% of the patients that had this information documented. In all patients, CGI scores improved from admission to discharge. As for side effects, one patient on LAI paliperidone had EPS and needed benztropine and another patient on the same LAIA was on benztropine due to a previous history of dystonia with haloperidol. No other side effects were described with the other LAIAs.

A combination of LAIAs was reported in three cases of adolescents with severe psychosis and aggression admitted in an adolescent forensic psychiatric unit [48]. All were males aged 16–17 years; one was already on LAIA, and the other two refused oral AP during their current hospitalization. One of them had a comorbid substance use disorder (glue sniffing and cannabis smoking). The AP used were the following: one patient was on LAI olanzapine 405 mg fortnightly together with LAI zuclopenthixol decanoate 600 mg fortnightly, another was on LAI paliperidone 150 mg monthly and LAI zuclopenthixol decanoate 400 mg fortnightly, and the last one on LAI paliperidone 150 mg monthly and LAI zuclopenthixol 600 mg fortnightly. Both LAI were administered the same day for all patients. These combinations decreased the Brief Psychiatric Rating Scales (BPRS) scores of each patient by almost 40 points. One patient showed mild parkinsonism and another showed polydipsia and polyuria without diabetes mellitus or diabetes insipidus. The other patient did not report any side effects.

Two cases of LAI paliperidone in adolescent inpatients were described by Fàbrega et al. [47]. One was diagnosed with undifferentiated schizophrenia and mild intellectual disability, and the other with psychotic disorder not otherwise specified (NOS) and conduct disorder. Both patients started treatment with oral paliperidone and then switched to LAI paliperidone 50 mg every 28 days (due to concerns about adherence and lack of insight), which was associated with an improvement of symptoms and a decrease in PANSS scores. LAIAs were begun due to the concerns regarding treatment adherence or a history of previous non-adherence. One patient did not report any side effects, and the other experienced an oculogyric crisis, after which oral biperiden 4 mg/day was added.

Looking at the single case reports, two of them were based on the description of side effects [44, 45]. Mirza et al. [45] described a male adolescent inpatient with schizophrenia who developed a severe acute-onset delirium after the second dose of LAI paliperidone (first dose: 150 mg and second: 100 mg). The treatment was associated with an improvement of his symptoms, but 10 days after the second dose the patient needed an admission due to fluctuating levels of consciousness and additional symptoms of delirium. No other cause for delirium was found. The case reported by Solfanelli et al. [44] focused on a skin rash, which was developed by an adolescent with schizophreniform disorder and comorbidity with juvenile idiopathic arthritis. After tolerating oral olanzapine, LAI olanzapine was initiated at a dosage of 300 mg every 3 weeks. Eight days after the first dose, a skin eruption was observed, with no other signs or symptoms, except for an increase in some liver function test results. After the administration of intramuscular betamethasone and oral chlorphenamine, the rash gradually disappeared and liver function test results returned to normal within a week.

In terms of effectiveness, the case of a 15-year-old incarcerated male diagnosed with schizophrenia and conduct disorder was described by Aggarwal and Lindegaard [43]. The subject was on oral aripiprazole 20 mg/day, with good response and tolerability, but after releasing from the center the patient stopped taking the medication and was reincarcerated after 3 months for other illegal behavior. After reintroducing oral aripiprazole, the LAI formulation was administered to improve adherence. After the new release, the patient continued being adherent and at 12-month follow-up the patient showed clinical stability, good tolerability, and no reincarceration.

Lastly, the case of an adolescent with schizophrenia starting LAI aripiprazole with two injections was reported [46]. A 16-year-old inpatient male experienced clinical improvement of the psychotic symptoms with aripiprazole 30 mg/day and clozapine 100 mg/day. Due to poor insight and comments about not taking medication after being discharged, LAI aripiprazole 800 mg (2 injections of 400 mg the same day) was administered as a fast way to reach the dose of 400 mg/monthly without oral supplementation. No side effects were observed. At 1-month follow-up, global functioning and insight had improved, as well as positive psychotic symptoms.

4 Discussion

This is, to our knowledge, the first systematic review conducted regarding the use of LAIA exclusively in children and adolescents with SSD. Despite the fact that this is a very important issue in clinical practice, we found few studies and case reports on this topic, as well as a scarce number of high quality studies. The largest number of reported cases were for LAI risperidone followed by LAI paliperidone. Clinical improvement was observed in almost all of the studies and case reports in the short and medium term (up to 12 months’ follow-up), with adequate tolerability. The existence and profile of side effects depended on the type of LAI prescribed. History of previous non-adherence, concern about poor treatment adherence, as well as lack of insight, were the main reasons for initiating LAIAs in all of the studies.

4.1 Efficacy/Effectiveness

LAIAs were linked to an improvement of clinical symptoms in most of the studies included, both with first-generation [40, 49] and second-generation drugs [28, 39,40,41,42,43,44,45,46] or with a combination of both [48]. Better functional outcome, and a smaller number of hospitalizations than with adolescents on oral AP were also reported after 12-month follow-up [37]. Only the study assessing the 1-year continuation rate described a higher number of discontinuations of LAI risperidone in early-onset versus adult-onset SSD, as an indirect way to measure effectiveness [42].

The use of LAIAs in adults with SSD has been consistently associated with improvement in clinical psychopathology, functionality and fewer relapses and hospitalizations compared with oral medication [18,19,20,21,22,23,24, 50]. It has to be taken into account that avoiding relapses and hospitalizations is important to elude clinical deterioration [51].

Mortality rates are also considered to be an important outcome for determining the long-term effectiveness of a medication [52]. LAIAs have been associated with less mortality than oral AP. In a nationwide register study conducted in Sweden including patients with schizophrenia aged from 16 to 64 years, second-generation LAIAs were associated with 33% less mortality than equivalent oral AP [53]. In a similar study (same age range and diagnosis) conducted with registry data in Taiwan, patients on LAIAs had lower risks of all-cause mortality, including natural-case mortality, and fewer suicide attempts compared with patients who were on the equivalent oral AP [54].

4.2 Safety/Tolerability

LAIAs have been reported to be a treatment option with a good tolerability profile in children and adolescents [32]. Reviewed studies on second-generation LAIAs described rates of side effects ranging from 0 (LAI aripiprazole) to 45% (LAI risperidone) [28, 38, 39, 41, 42], but only one study compared different LAIAs [28]. This study which used first-generation LAIAs showed side effect rates of 47.6% [40]. Weight gain, sedation, EPS, hyperprolactinemia and depression were the most prevalent side effects in the reviewed second-generation LAIA studies [28, 38, 39, 41], while EPS were the most frequent in first-generation LAIAs [40]. None of the studies reviewed compared patients with first-generation LAIA to those on second-generation LAIAs. When comparing first- to second-generation LAIAs in adults with SSD, no differences were observed in tardive dyskinesia and parkinsonism; however, second-generation LAIAs were associated with less prescription of antiparkinsonian agents [50]. On the other hand, long-term weight gain and body mass index were greater with second-generation than with first-generation LAIAs [50].

4.3 First Episode of Psychosis

First episode of psychosis is an earlier stage of a possible severe mental disease [55], after which most patients go on to develop either SSD or bipolar disorder, although 58% of cases develop no further episodes over 5.5 mean years of follow-up, according to a systematic review and meta-analysis of studies with adult patients [56]. In this stage, the prevention of relapses is decisive to help avoid deterioration and improve clinical and functional outcomes [55]. In a recent study in adults, patients in the early stage of their disease who had indicators of poor prognosis such as homelessness, legal problems or substance use disorder seemed to benefit from the early prescription of LAIAs, with a reduction and delay in relapses and rehospitalizations compared to patients with good prognosis on oral AP [51]. Moreover, in a systematic review and meta-analysis of studies with adults, patients with first-episode psychosis on LAIAs had less risk of relapse, with a relative risk (RR) of 0.58 (95% confidence interval [CI] 0.34–1.01), and with no differences between first-generation and second-generation LAIAs [18]. However, rates of hospitalization were similar between patients on LAIAs and oral AP, with an OR of 0.57 (95% CI 0.30–1.08) [18]. In adolescents, Petrić et al. observed fewer hospitalizations and higher personal and social functioning in patients with first-episode psychosis on LAI paliperidone compared with those on oral risperidone [41].

4.4 Resistant Schizophrenia Spectrum Disorders (SSD)

The definition of resistant SSD includes an inadequate response to at least two AP trials of sufficient dose and duration and having ruled out non-adherence to treatment [57]. The American Academy of Child and Adolescent Psychiatry specifies the importance of reviewing (apart from the child’s clinical status) the treatment history, in order to ensure that the case is effectively considered to be resistant SSD [4]. The Indian guidelines also set out that if a patient fails to respond to particular antipsychotic medication, adherence to medication needs to be evaluated before changing the medication [58]. Clozapine is the treatment recommended for resistant SSD, both in adults [59] and in minors [4, 25]. When patients are resistant to clozapine, the use of LAIAs has been proposed as an augmentation strategy for children and adolescents with resistant SSD [60]. In adults, a mirror-image retrospective study showed that adding a first- or second-generation LAIA to clozapine treatment reduced the number of relapses, as well as the number and length of hospitalizations. Furthermore, no changes in analytical parameters, such as neutrophil counts or prolactin levels, were observed with the combination of treatments [61]. In a similar design also with adult patients, Bioque et al. [62] reported that adding LAI paliperidone to clozapine improved clinical symptoms, functionality, number and length of hospitalizations, number of visits to emergency services, and severity of side effects.

In the studies reviewed, no response or only partial response to multiple oral medication trials, which is generally considered resistant SSD, was one of the reasons for prescribing LAIAs [40].

4.5 Comorbid Substance Use

The comorbidity of a substance use disorder with SSD is high, reaching 41.7% in a systematic review [63]. It has been consistently reported that patients with substance use disorders have an earlier age at onset of SSD [63, 64]. In our reviewed studies, some of the studies reported substance use [28, 41, 48, 49] with rates ranging between 27.8% and 86% of the samples. Only one study had a diagnosis of substance dependence 3 months before initiating the study as an exclusion criterion [38].

Substance use comorbidity leads to poorer outcomes for SSD patients and the best prognosis is achieved when combined AP treatment and psychosocial intervention are implemented [65]. In a 3-year study comparing patients with a first-episode of psychosis and comorbid substance use who started LAIAs as a first-line medication versus those on oral AP, patients on LAIAs had a significantly lower relapse rate and higher relapse-free survival time, as well as trends for reduced rehospitalization rates and hospitalization-free survival time [66].

4.6 Reasons for Starting Long-Acting Injectable Antipsychotics (LAIAs)

In all but one [38] of the studies reviewed, a previous history of non-adherence, concerns about adherence to medication or lack of insight were the main reasons for starting LAIAs [28, 39,40,41,42,43,44,45,46,47,48,49]. Aggressive behavior as well as severe resistant psychopathology were also reasons for starting LAIAs [40, 48].

Initially, LAI formulations of AP were developed to improve adherence [67], which is crucial in order to guarantee effective treatment of patients [68]. Pediatric patients, particularly adolescents, have a higher risk of non-adherence to psychotropic medication [68]. This is a problem of particular clinical importance among adolescents, since a median of 33% (ranging from 6 to 62%) of non-adherence in this age group was reported in a systematic review [69]. A study in adolescents, including 53.7% with SSD, reported 9% of poor and 25.4% of moderate treatment adherence, showing a highly significant association between a patient’s attitude towards the drug and adherence [70]. Other situations such as substance abuse, violence or legal conflicts are also risk factors for lack of adherence [12, 13, 71, 72]. Adolescents placed in foster care could be another indicator for considering the use of LAIA, due to a higher risk of non-adherence, and increased incidence of behavioral difficulties and substance use comorbidities [73]. In fact, youth in foster care comprised 23.3% of the patients included in one of the studies reviewed [28] and 16% of the children and adolescents with at least one prescription of LAIA in the study conducted in the Indiana Medicaid system [74].

An additional factor to be taken into account regarding the prescription of LAIAs is lack of insight. This is a frequent clinical characteristic of patients with early-onset SSD [75, 76], and usually refers to subjects’ lack of awareness regarding their mental disorder and the need for treatment [77]. Insight is associated with adherence to treatment [77]. Worse insight has been associated with more severe symptoms, increased risk of discontinuing treatment, and poorer outcomes [74, 78, 79]. Significantly, it has also been suggested that younger patients may have less insight than adults with SSD [75, 76, 80].

4.7 The Potential Role of LAIAs in the Treatment of Children and Adolescents with SSD

Several recommendations can be put forward based on existing knowledge concerning the use of LAIAs in children and adolescents with SSD (aged >12 years). The strength of the evidence of the recommendations are rated below:

  1. 1.

    LAIAs could be a helpful option for young people who are non-adherent with oral antipsychotic medication (Low).

  2. 2.

    Patients with poor insight could be monitored for non-adherence, and LAIAs should be kept in mind as a possible treatment option (Low).

  3. 3.

    If, with oral medication, patients experience side effects while showing an improvement in terms of symptoms and functioning, a switch to the same medication in an LAI formulation may improve tolerability. If the existing oral AP does not have an LAI formulation, a switch to a different oral AP with an available LAI formulation may also be beneficial (Very low).

  4. 4.

    Comorbid substance use could be taken into account when an AP is initiated, keeping in mind that LAIAs can be a helpful option in the presence of this comorbidity (Low).

  5. 5.

    Patients with a recent or first episode of psychosis may also benefit from the use of LAIAs. This treatment option need not only be considered an option for patients with a long duration of their disease (Low).

  6. 6.

    In resistant or severe SSD, a switch to LAI formulation may help improve the effectiveness of AP treatment in some patients (either in monotherapy or combined with oral AP) (Very low).

Apart from the potential role of LAIAs that has been pointed out, it is important to remember that patients and caregivers’ preferences should be taken into account to help promote shared decision making [81]. Patients and their caregivers should be consulted about LAIAs when a therapeutic plan is being developed.

4.8 Limitations and Strengths

The main limitations of this systematic review are the lack of randomized controlled trials (RCTs), the heterogeneity of the designs of the studies (open-label trial, observational prospective, observational retrospective, case series, case reports), and the small number of articles included. Moreover, some of the original studies were of low quality and had an unclear risk of bias according to the rating scales we used, and none of the studies reviewed was a randomized control trial. Furthermore, the studies examined a limited number of young patients with SSD on LAIAs, none were < 12 years of age, and there was a narrow range of different LAIAs and doses used (i.e., only two patients were on LAI olanzapine), but this could reflect typical clinical practice. Also, one study included stable patients who switched from oral AP to LAI risperidone [38] while in the other studies patients on LAIA, or switched to LAIA, were actively psychotic [28, 39,40,41,42,43,44,45,46,47,48,49]. Lastly, the means by which adverse events were evaluated as part of these reports may have led to the under-reporting of these events. Apart from body weight measure and prolactin levels in some of the studies and three original studies which used a scale [38, 39, 41], adverse events were self-reported. Among the strengths of our study is the fact that the review looks at the use of LAIA exclusively in children and adolescents with SSD. Also, the review followed the internationally accepted PRISMA criteria and was registered in the PROSPERO database.

5 Conclusion

To our knowledge, this is the first systematic review to address exclusively the role of LAIAs in the treatment of children and adolescents with SSD. Overall, although no RCT studies were found and the quality of most of the studies was low, they documented good effectiveness and acceptable tolerability in treating these patients, with a different pattern of side effects according to the type of LAIA. No studies included patients younger than 12 years. The use of this type of AP formulation in this population requires further study, ideally with other prospective and controlled designs, in order to more fully understand the potential role that LAIAs could play in the treatment of children and adolescents with SSD.