Long-Acting Injectable Antipsychotics in Children and Adolescents

Abstract

Objective:

While a number of articles have reviewed the use of long-acting injectable antipsychotics (LAIs) in first-episode psychosis, there has been extremely limited focus on LAIs in children and adolescents. This review of the literature evaluated use of LAIs in children and youth under the age of 18.

Methods:

We conducted a comprehensive search of the PubMed, PsychINFO, CINAHL, and EMBASE databases using keywords related to LAIs, children, and psychiatric conditions, including schizophrenia, bipolar disorder, and schizoaffective disorder. Reports were included if they were in English, conducted between 1971 and 2015, and reported on use of LAIs in individuals less than the age of 18.

Results:

The search identified seven reports including one open-label trial, three case reports, and three case series. No controlled trials were found. Sample sizes ranged from 1 to 19 with a total of 36 individuals in all cases combined. Mean sample age was 12.1 ± 2.2 in the open-label trial and calculated to be 14.9 ± 1.5 in the remainder of the reports. Most patients (80.6%) were boys. Primary diagnoses included bipolar I disorder (n = 18; 50%), schizophrenia (n = 7; 19.4%), and bipolar spectrum disorders (n = 6; 16.6%). The LAIs used were risperidone long-acting injection (n = 24; 66.7%), paliperidone palmitate (n = 8; 22.2%), fluphenazine decanoate (n = 1; 2.8%), aripiprazole extended-release injectable (n = 1; 2.8%), zuclopenthixol decanoate (n = 1; 2.8%), and olanzapine extended release (n = 1; 2.8%). Most cases reported clinical improvement and the majority of individuals (n = 14; 82.4%) were reported to tolerate the medication well. The most common side effects were weight gain (mean 5.7 ± 4.1 kg in the open-label trial), tremor (n = 2; 5.6%), and oculogyric crisis (n = 2; 5.6%).

Conclusions:

This literature review suggests that LAI use in youth with serious mental illness may improve clinical outcomes and adherence. Side effects of LAIs among youth appear are similar to oral preparations. However, there is a paucity of data despite issues with nonadherence in youth and the fact that they have much to lose and much to gain. Existing reports have substantial methodological limitations, and research is needed to guide the use of LAIs in children and adolescents.

Introduction

Antipsychotics are a mainstay of treatment for a number of disorders in children and adolescents, including schizophrenia, bipolar disorder, autism spectrum disorder, and Tourette's disorder (Correll et al. 2011). Many oral, short-acting forms of these medications are approved for use in youth with these disorders (Correll et al. 2011).

In adults, long-acting injectable forms of these antipsychotics are approved for the treatment of schizophrenia, schizoaffective disorder, and bipolar disorder (Citrome 2013). However, no long-acting injectable antipsychotics (LAIs) are currently approved for use in youth despite evidence that many serious mental health disorders have their onset during childhood or adolescence (Kessler et al. 2007; Driver et al. 2013). Some experts have suggested that LAIs be used earlier and more frequently than they currently are, particularly in nonadherent children and adolescents (Chue and Emsley 2007; Lachman 2014; Stevens et al. 2014).

Irrespective of type of treatment employed, there is strong evidence to support that early and adequate interventions to treat mental health disorders are important in optimizing good outcomes, particularly in youth. For example, evidence suggests that clinical, functional, and psychosocial decline often occurs within the first few years after the onset of psychosis and a longer duration of untreated illness can have negative impacts on outcome (Birchwood et al. 1998; Harris et al. 2005; Marshall et al. 2005; Perkins et al. 2005; Crumlish et al. 2009). In addition, structural changes in the brain may occur progressively during the course of schizophrenia and are thought to be associated with the duration of untreated psychosis (Puri 2010; Emsley et al. 2013). Similarly, evidence suggests that the duration of untreated bipolar disorder is associated with poorer clinical outcomes (Medeiros et al. 2016).

Addressing periods of untreated illness may be particularly important in youth as adolescence is a time during which multiple developmental processes occur, including, but not limited to, frontal lobe development (impacting executive functioning), increased independence, development of intimate relationships, abstract thinking development, and identity formation (Giedd et al. 1999; Martin and Volkmar 2007; and Taylor et al. 2015). These critical developmental processes emphasize the importance of early and effective treatments of disorders such as schizophrenia, schizoaffective disorder, and bipolar disorder in youth.

Medication nonadherence is often a challenge and common factor contributing to relapse and recurrence in medicine as a whole and in psychiatric disorders in particular. For example, treatment adherence rates for first-episode psychosis are consistently reported to be <50% and lack of adherence is a common cause of relapse and rehospitalization in schizophrenia (Verdoux et al. 2000; Thieda et al. 2003; Coldham et al. 2006; Alvarez-Jimenez et al. 2012). Hack and Chow (2001) found that children are at an even higher risk for nonadherence than adults, with adolescents being a particularly vulnerable group.

In addition, one study in youth with bipolar disorder reported that only 34.2% of patients were fully adherent to their medication regimen (Coletti et al. 2005). Pogge et al. (2005) also reported that only 45% of hospitalized adolescents remained compliant with atypical antipsychotics. The authors describe adolescents as having a unique set of factors related to nonadherence, including developmental temperament, parental preference, and physician involvement (Pogge et al. 2005). Discontinuation of antipsychotic medication for first-episode schizophrenia and schizoaffective disorder has been shown to increase the risk of relapse by nearly five times (Robinson et al. 1999). Poor adherence can lead to poor clinical outcomes, including worsening disease progression, family discord, and risk of harm to self and others (Bera 2014).

Some emerging evidence suggests that the use of LAIs early in the course of schizophrenia may improve adherence and help reduce the incidence of relapse, decrease hospitalization rates, and improve prognosis (Kim et al. 2008; Weiden et al. 2009; Viala et al. 2012; Marcus et al. 2015). In addition, there is some evidence that there is a reduced risk of emergency room visits and hospital readmission for adults who are receiving LAIs rather than oral antipsychotics (Lafeuille et al. 2015). Naturalistic and observational studies regularly show this superiority of LAIs over oral antipsychotics (Kishimoto et al. 2013). For example, Tiihonen et al. (2011) found that in a naturalistic, prospective cohort study, patients receiving LAIs had an approximately one-third risk of rehospitalization compared to those receiving oral antipsychotics.

Large, randomized controlled trials (RCTs) of oral antipsychotics versus LAIs have had mixed results, however (Kishimoto et al. 2014). Kishimoto's meta-analysis of 21 RCTs of LAIs versus oral antipsychotics did not show superiority of the LAIs in relapse prevention or nonadherence. The authors suggested that RCTs, by nature, may improve adherence in all patients, irrespective of type of medication administered (Kishimoto et al. 2014). To address this concern, the same authors conducted a meta-analysis of mirror studies, a design intended to more closely resemble naturalistic clinical practice. This analysis concluded that LAIs were statistically superior to oral antipsychotics in reducing the number of hospitalizations and preventing hospitalization overall (Kishimoto et al. 2013). Similarly, Kirson et al. (2013) found that LAIs performed better in nonrandomized, naturalistic settings but were nonsuperior in formal RCTs. Both authors called for ongoing research with varied designs to continue to explore the benefits of LAIs versus oral antipsychotics (Kirson et al. 2013; Kishimoto et al. 2013).

Despite evidence that LAIs may be indicated for first-episode psychosis, the majority of psychiatrists do not use LAIs for first-episode psychosis (Heres et al. 2006; Jaeger and Rossler 2010) for adults, and there is very limited research on the use of LAIs in youth. While a number of articles have described the use of LAIs in first-episode psychosis (Bartzokis et al. 2011; Kim et al. 2012; Jeong and Lee 2013; Heres et al. 2014), none, to the best of our knowledge, has focused on LAIs in children and adolescents. Therefore, we undertook a review of the available literature to determine what the current state of knowledge is for the use of LAIs in children and adolescents.

Methods

We conducted a comprehensive search of the PubMed, PsychINFO, CINAHL, and EMBASE databases (1971–2015) (Fig. 1). The following keywords were used as our search terms: long-acting, injectable, injection, delayed-action, depot, antipsychotic, LAI, neuroleptic(s), child, children, adolescent(s), youth, pediatric, psychosis, psychotic, mania, schizophrenia, schizophreniform, schizoaffective, and bipolar disorder. The results (either abstracts or full-text articles) were retrieved and reviewed for relevance. The reference lists of relevant papers were hand searched for relevant articles. We included all studies published in English in which LAI use was reported in children and/or adolescents. In addition, we were made aware of a case series in press and included this in our review. Studies that included adolescents, but were not exclusive to this age group were not included in the analysis as these were found to be focused on early psychosis (and included adults) and had a mean age well above the area of interest. Some studies did not specify the age of included individuals and these were excluded as well.

FIG. 1.

Search parameters for LAI use in children and adolescents. LAI, long-acting injectable antipsychotic.

Results

Our comprehensive search of the PubMed, PsychINFO, CINAHL, and EMBASE databases found 132 articles with an additional 95 articles identified through an additional hand search. After deduplication and exclusion of 62 irrelevant articles, 133 full-text articles were reviewed for inclusion. Those that included only adults (72), were reviews or editorials (15), did not report on LAIs (13), or did not specify the age of individuals (1) were excluded. In addition, 23 articles that included youth and adults, but did not stratify results by age, were excluded (Fig. 1).

Overview of findings

The search identified a total of seven reports with one open-label trial, three case reports, and three case series that reported on LAI use in children and adolescents (Table 1) (Erermis et al. 2007; Fu-I et al. 2009; Wisniewski 2012; Boarati et al. 2013; Patel et al. 2013; Fabrega et al. 2015; Pope and Zaara 2016). No controlled trials were found. The relevant studies were published between 2007 and 2016, with only two published before 2012. Three of these reported on cases in an outpatient setting, three reported on cases primarily in an inpatient setting, and the other did not specify the setting.

Table 1.

Results of Comprehensive Review of Long-Acting Injectable Antipsychotics in Children and Adolescents

Study	Diagnostic subtype (n)	Methodology	Duration/setting	N	Mean age (range)	Males (%)	Medication (dose)	Efficacy outcomes	Adverse effects	Discontinuation rates
Boarati et al. (2013)	BPI (17), BP NOS (2)	Open label	6 Months/outpatient	19	12.1 ± 2.2 (NR)	84.2	RLAI (mean 25–46.3 mg)	Improvement in global functioning and symptom severity (CGAS 20.6 vs. 42.9, p < 0.0001 and CGI-S 5.9 vs. 3.4, p < 0.0001)	Weight gain (mean 5.7 ± 4.1 kg), increased appetite, tremor (n = 2), oculogyric crisis (n = 1)	26% Discontinued (by 2 months); 74% continued
Pope and Zaara (2016)	BPI (1), BP NOS (1), schizophrenia (5), schizoaffective disorder (1), mood disorder NOS (1)	Case series	NR/inpatient	9	15.4 ± 1.0 (14–17)	77.8	RLAI, fluphenazine decanoate, paliperidone palmitate, aripiprazole extended release	Clinical improvement and discharge from hospital (mean admission CGI-S 5.67; mean discharge CGI-S 2)	Extrapyramidal symptoms (n = 1)	0%
Fu-I et al. (2009)	Bipolar disorder (3)	Case series	60–165 Days/NR	3	11.3 ± 4.6 (11–14)	100	RLAI (25 mg)	Clinical improvement (mean baseline CGI 6.33; mean follow up CGI 2.33)	NR	0%
Erermis et al. (2007)	Bipolar disorder	Case report	NR/outpatient	1	14	0	Zuclopenthixol decanoate	N/A	NMS	Discontinued after 2 days
Patel et al. (2013)	Mania	Case report	1 Month/outpatient	1	16	0	RLAI (37.5 mg)	Clinical improvement	Elevated prolactin levels, galactorrhea, hirsutism	Discontinued after second injection
Fabrega et al. (2015)	Undifferentiated schizophrenia (1); psychotic disorder NOS (1)	Case series	NR/inpatient	2	15.5 ± 2.1	100	Paliperidone palmitate (50 mg); zuclopenthixol decanoate (100 mg)	Improvement in symptoms; discharge from hospital (n = 2)	Oculogyric crisis, difficulty concentrating and somnolence (n = 1)	One discontinued, but restarted LAI
Wisniewski (2012)	Paranoid schizophrenia	Case report	2 Months/inpatient	1	15	100	Olanzapine extended release	Decreased positive and negative symptoms of schizophrenia, improved social functioning	NR	0%
Summary	Bipolar spectrum 72% Schizophrenia 19.4% Schizoaffective 2.8% Mood NOS 2.8% Psychotic disorder 2.8%	One open label Three case series Three case reports	Length of treatment: 1–6 months	Total: 36	Weighted mean age 13.29	80.6	RLAI (n = 24; 66.7%; dose range 25 mg up to a mean dose of 46.3 mg); paliperidone palmitate (n = 8; 22.2%; dose range 50–234 mg); fluphenazine decanoate (n = 1; 2.8%; dose 6.25 mg); aripiprazole extended-release injectable (n = 1; 2.8%; dose 400 mg); zuclopenthixol decanoate (n = 1; 2.8%; dose 200 mg); olanzapine extended release (n = 1; 2.8%; dose range 210–300 mg)	Clinical improvement (as rated by CGAS and CGI-S [mean reduction 3.42]), decreased positive and negative symptoms of schizophrenia, improved social functioning	Most common: weight gain (mean 5.7 ± 4.1 kg), increased appetite. Mild transient tremor (n = 2), oculogyric crisis (n = 2), drowsiness (n = 1), NMS (n = 1), elevated prolactin (n = 1)	Overall discontinuation rate: 22.2%

BPI, bipolar I disorder; BP NOS, bipolar disorder not otherwise specified; CGAS, children's global assessment scale; CGI-S, clinical global impressions severity of illness scale; LAI, long-acting injectable antipsychotic; N/A, not applicable; NMS, neuroleptic malignant syndrome; NR, not reported; RLAI, risperidone long-acting injection.

Sample sizes ranged from 1 to 19 youth with a total of 36 individuals included in the reports. The age range was 11–17. Mean sample age was 12.1 ± 2.2 in the open-label trial and calculated to be 14.9 ± 1.5 in the remainder of the reports. The demographic composition of the entire sample was 29 (80.6%) boys and 7 (19.4%) girls. While the majority of reports did not comment on the race of the individuals, 19 (52.8%) were from Brazil, 13 (36%) were from the United States of America, 2 (5.6%) were from Spain, 1 (2.8%) was from Poland, and 1 (2.8%) was from Turkey.

Diagnoses included bipolar I disorder (BPI; n = 18; 50%), schizophrenia (n = 7; 19.4%), bipolar disorder not otherwise specified (BP NOS; n = 3; 8.3%), and “bipolar disorder” (with no classification listed; n = 3; 8.3%). One individual was diagnosed with each of the following: schizoaffective disorder, mood disorder NOS, psychotic disorder NOS, “mania with psychotic features,” and “psychotic features.” The LAIs used in these reports were risperidone long-acting injection (RLAI; n = 24; 66.7%; dose range 25 mg up to a mean dose of 46.3 mg), paliperidone palmitate (n = 8; 22.2%; dose range 50–234 mg), fluphenazine decanoate (n = 1; 2.8%; dose 6.25 mg), aripiprazole extended-release injectable (n = 1; 2.8%; dose 400 mg), zuclopenthixol decanoate (n = 1; 2.8%; dose 200 mg), and olanzapine extended release (n = 1; 2.8%; dose range 210–300 mg).

In the open-label study, there was significant improvement in global functioning and symptom severity (children's global assessment scale [CGAS] 20.6 vs. 42.9, p < 0.0001 and clinical global impressions severity of illness scale [CGI-S] 5.9 vs. 3.4, p < 0.0001, respectively) (Boarati et al. 2013), and clinical improvement was noted in the majority of individuals (n = 16, 94%) in the case reports/case series. The CGI-S was used in 12 cases with a mean reduction in CGI-S of 3.42. In the open-label trial, weight gain (mean 5.7 ± 4.1 kg) and increased appetite were the most common adverse effects. In addition, two patients were reported to have mild transient tremor and one patient was reported to have an oculogyric crisis that resolved (Boarati et al. 2013). Among the remainder of the cases, treatment with an LAI was noted to be well tolerated in 14 (82.4%) individuals with no adverse effects reported. One individual was noted to have drowsiness, difficulty focusing, and an oculogyric crisis, one individual experienced neuroleptic malignant syndrome (NMS), and one had elevated prolactin, hirsutism, and galactorrhea.

Specific reports

The one open-label study that examined the use of LAIs in youth was a 6-month study of RLAI in 19 outpatient children and adolescents (mean age 12.1 ± 2.2) with a diagnosis of BPI, bipolar II disorder (BPII), or BP NOS presenting with severe pediatric bipolar disorder symptomology (as measured by the CGI-S) and severe functional impairment (as measured by the CGAS) (Boarati et al. 2013). Participants were required to have previously used an oral formulation of risperidone with good tolerability. Youth with comorbid pervasive developmental disorders, schizophrenia, or intellectual disability (IQ <70) were excluded. Before the study, 57.9% of the patients were noted to have adherence problems and 42.1% had failed previous oral medication trials. After enrollment, 5 patients (26%) dropped out during the first 2 months and 14 (74%) completed the entire 6-month study. There was significant improvement in global functioning and symptom severity (CGAS 20.6 vs. 42.9, p < 0.0001 and CGI-S 5.9 vs. 3.4, p < 0.0001, respectively), with improvements noted at 2 months and maintained over the remainder of the study. The most common adverse events were weight gain (mean 5.7 ± 4.1 kg) and increased appetite. Other reported adverse effects were high prolactin levels, mild transient tremors, and transient oculogyric crisis (Boarati et al. 2013).

One retrospective chart review reported on nine youth (mean age 15.4 ± 1.0; range 14–17; two girls, seven boys) started on LAIs during an inpatient hospitalization. All individuals were receiving an LAI for the first time (Pope and Zaara 2016). LAIs included risperidone (n = 1), fluphenazine (n = 1), paliperidone palmitate (n = 6), and aripiprazole (n = 1). Diagnoses included BPI (n = 1), BP NOS (n = 1), schizophrenia (n = 5), schizoaffective disorder (n = 1), and mood disorder not otherwise specified (n = 1). Comorbid diagnoses included post-traumatic stress disorder, cannabis abuse, and attention-deficit/hyperactivity disorder (ADHD). All, but one patient had been on at least one other prior antipsychotic medication and had a history of nonadherence. All patients tolerated the LAI well and showed clinical improvement with a mean decrease in CGI-S of 5.67–2 from admission to discharge. One patient developed extrapyramidal symptoms treated with benztropine. No adverse events led to discontinuation of LAI and all patients were discharged with plans to continue LAI at community mental health agencies (Pope and Zaara 2016).

One case series reported on three youth, aged 11, 14, and 14 (mean age 11.3 ± 1.3) with bipolar disorder and a history of non-adherence (Fu-I et al. 2009). Each child was started on RLAI dosed at 25 mg every 2 weeks. All three children had improvement in their CGI over time with length of treatment 10, 36, and 24 weeks, respectively. The mean baseline CGI was 6.33 and mean follow-up CGI was 2.33, suggesting an overall improvement in clinical symptoms. The youth tolerated the medication well and no significant changes in cholesterol and prolactin levels were reported (Fu-I et al. 2009).

Erermis et al. (2007) reported on a 14-year-old girl presenting with altered mental status, delusions of reference, auditory and visual hallucinations, agitation, aggression, irritability, dysphoria, and mood lability. She initially received 200 mg of zuclopenthixol decanoate. She subsequently developed symptoms consistent with NMS and was treated with bromocriptine and diazepam, which led to clinical improvement (Erermis et al. 2007).

Another case report described a 16-year-old girl with new-onset mania with psychotic features, who was treated in an outpatient setting with RLAI 37.5 mg every 2 weeks (Patel et al. 2013). She had clinical improvement, but after the second dose of LAI developed elevated prolactin levels, galactorrhea, and hirsutism, leading to LAI discontinuation. Galactorrhea resolved after 1 week and hirsutism resolved after 1 month (Patel et al. 2013).

A final case series reported on two adolescents treated with paliperidone palmitate (Fabrega et al. 2015). In this report, one hospitalized 14-year-old boy with undifferentiated schizophrenia was started on LAI due to concerns about nonadherence. The LAI was initiated at 50 mg and later maintained at 50 mg every 28 days. He was discharged from the hospital after 17 days. One year later, he remained on medication, showed functional improvement, and had no adverse effects.

The other patient in this study was a 17-year-old boy with psychotic disorder NOS, multiple psychiatric admissions, and treatment nonadherence. Paliperidone palmitate 50 mg resulted in symptoms, including oculogyric crisis (that resolved with anticholinergic treatment), concentration difficulties, and somnolence, leading to patient declining further injections, although he was discharged from the hospital after 14 days. During a subsequent admission, he was started on zuclopenthixol decanoate 100 mg every 14 days. He subsequently reported a return in somnolence and difficulty concentrating, and was switched to an oral second-generation antipsychotic. He again became nonadherent and was again started on the LAI paliperidone palmitate in conjunction with an anticholinergic medication. No details were provided regarding the outcome of this last introduction of LAI (Fabrega et al. 2015).

The final case report described a 15-year-old male with a 2-year history of paranoid schizophrenia, frequent psychiatric hospitalizations, multiple failed trials of oral antipsychotic medications, a failed trial of RLAI, and medication nonadherence (Wisniewski 2012). He was started on olanzapine extended-release injections 210 mg every 15 days and increased to 300 mg after 2 weeks. After 2 months, he showed a reduction in positive and negative symptoms of schizophrenia as well as improved social functioning. He was reported to tolerate the drug well, with no adverse effects reported (Wisniewski 2012).

Discussion

Evidence for the use of LAIs in children and adolescents is extremely limited. This first literature review of LAI use in children and adults found only seven published reports, including one open-label trial, three case reports, and three case series. The majority of publications was within the last 5 years, reflecting the increasing availability of LAI in clinical practices setting. Most young people prescribed LAIs were adolescents and most had a primary diagnosis of BPI (50%) and schizophrenia (19.4%). The majority of published studies found in our review involved young people who were highly symptomatic, often at risk of harm to others or to themselves, and were established to be nonadherent or poorly adherent with oral antipsychotic drugs. This is consistent with the American Academy of Child and Adolescent Psychiatry recommendation that LAI use be considered in adolescents with schizophrenia with chronic symptoms and a history of nonadherence (McClellan et al. 2013).

It has been noted that off-label use of antipsychotic medication is not uncommon in the pediatric population (Schneider et al. 2014). This review found that LAIs are also being used off-label in children and adolescents, particularly in bipolar disorder and schizophrenia. The need for evaluating the impact of LAIs in children with mental disorders and/or disruptive or harmful behaviors, rather than simply extrapolating adult data to children, is similar to what has been identified with oral antipsychotic drugs (Findling et al. 2006; Cohen et al. 2012).

These studies reported on a variety of conditions, including bipolar spectrum disorder, schizophrenia spectrum disorders, mood disorder NOS, and schizoaffective disorder, for which LAIs were efficacious. Youth in a variety of settings, including outpatient and inpatient, were treated with LAIs and those with severe mental illness who were started on LAIs were able to be discharged on these medications. Individuals who had previously been nonadherent were maintained for up to 6 months on an LAI. These studies begin to suggest that the use of LAIs in youth may improve acute clinical outcomes, increase adherence, and decrease the risk of relapse. However, due to the small number of studies and their open-label nature, their findings must be interpreted cautiously.

Preliminary evidence from this literature review suggests that LAI tolerability appears relatively similar to reports of oral drugs with similar side effects in young people with psychiatric conditions. Common side effects appear primarily to include extrapyramidal symptoms, increased appetite, weight gain, sedation, and endocrine side effects such as elevated prolactin and galactorrhea. These adverse effects are the same as those seen in oral formulations of atypical antipsychotic drugs, suggesting they are related to the antipsychotic medication profile and not to the injectable formulation used (Correll 2008). Tolerability of LAIs in youth was reported up to 6 months after initiation and none of the reports identified nonadherence as a reason for medication discontinuation.

There are often barriers to the use of LAIs in youth. These can include a child or guardian's preference for an oral medication, limited access to injection support at community clinics, and insurance coverage issues (Getzen et al. 2014). However, at least one study reported specifically that youth and their caregivers are open to the option of LAI treatment (Correll et al. 2013), and the studies reported herein also suggest that patients and caregivers are willing to consider LAIs. Insurance coverage, at times, is influenced by the amount of research supporting the use of a particular form of a medication in a population, and further research into LAIs in youth could improve access.

As described in this literature review, few studies have examined the tolerability and efficacy of LAIs in children and adolescents. Those that are available suggest that in some cases, their use could offer an opportunity to make a robust and positive difference in long-term outcomes and health trajectories for youth with a variety of mental health conditions. Young people have both much to lose and gain with respect to being able to master developmental tasks such as establishing independence, setting and achieving personal and occupational goals, and minimizing the destructive effect of stigma associated with psychiatric relapse and disability.

Finally, the literature to date focuses on children and adolescents who were at highest risk for nonadherence or had failed multiple medication trials. Although this seriously ill population shows some evidence for the safe use of LAIs, it is difficult to translate these data into patients who have not failed as many medications and are not at such acute risk. LAI use may be useful in populations of youth with serious mental illness who are at risk for relapse and nonadherence, but have less risk factors than those studied to date. Expanding the clinical population studied and applying more vigorous study designs would benefit the future research into the use of LAIs in children and adolescents.

Limitations of this review include that it was not systematic and therefore there is a possibility that some studies were missed. However, it is unlikely that many more articles would have been found that are relevant to this topic. Due to the small number of studies found and their non-RCT nature, any finding must be interpreted cautiously. In addition, the small number of individuals as well as the fact that all were nonadherent with oral medications before the use of LAIs make extrapolation of data to medication-naive individuals difficult.

Conclusions and Clinical Significance

This report provides the first review of LAI use in children and adolescents. While there are limited data available, the results suggest that LAIs in youth with bipolar spectrum disorders, schizophrenia, and schizoaffective disorder may be safe and efficacious with the added benefit of increasing adherence in this high-risk population.

Footnotes

Acknowledgment

We would like to acknowledge the valuable assistance of Jennifer Staley, MLIS, who assisted in obtaining articles.

Disclosures

Neither S.L. nor M.M. has competing financial interests. M.S.: Research grants within past 3 years: Pfizer, Merck, Ortho-McNeil Janssen, Janssen, Reuter Foundation, Woodruff Foundation, Reinberger Foundation, National Institute of Health (NIH), and Centers for Disease Control and Prevention (CDC). Consultant: Bracket, Prophase, Otsuka, Pfizer, and Sunovion. Royalties: Springer Press, Johns Hopkins University Press, Oxford Press, UpToDate, and Lexicomp. CME activities: American Physician's Institute, MCM Education, CMEology.

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