Initiation of Aripiprazole Lauroxil Long-Acting Injectable in Adolescents During Hospitalization: A Case Series

Abstract

Objective:

The efficacy and safety of long-acting injectable (LAI) antipsychotics in the pediatric population is not well established due to limited evidence. This case series aims to describe off-label use of aripiprazole lauroxil (AL) LAI in adolescent inpatients, including findings on safety and readmission trends.

Methods:

This was a retrospective chart review of patients who were initiated on AL LAI while admitted at a county-based adolescent psychiatric unit between March 2021 and March 2023. Data comprised sociodemographic and clinical characteristics, such as psychiatric diagnoses, prior antipsychotic trials, and history of nonadherence. Other observations of interest included tolerability of AL LAI and time to readmission.

Results:

This analysis identified 12 adolescents who received AL LAI within a 2-year period. The mean age was 16 ± 1 years, and seven (58%) patients were female. There were varying primary psychiatric diagnoses, with the most common being bipolar disorder (25%), schizophrenia (17%), major depressive disorder with psychotic features (17%), and unspecified mood disorder (17%). Eleven (92%) patients had previously trialed at least one antipsychotic, with seven (58%) having exposure to oral aripiprazole before admission. Nonadherence was the driving factor for LAI consideration in all but one patient. AL LAI was well tolerated short term; one patient reported experiencing injection site pain, and one patient discontinued the LAI after discharge due to anxiety. Time to readmission ranged from 15 to 658 days for seven patients who were hospitalized again; two of the readmissions occurred within 1 month.

Conclusion:

This is the first case series to describe initiation of AL LAI at an inpatient adolescent psychiatric unit. Our study illustrates that AL LAI may hold potential as an acceptably tolerated treatment in adolescents with varying psychiatric diagnoses. Further studies are needed to evaluate long-term safety and effectiveness of AL LAI in youth.

Introduction

Oral aripiprazole has been well studied in pediatric patients with several approved indications, but there is little information regarding the use of long-acting injectable (LAI) aripiprazole in youth. Both available LAI formulations, aripiprazole monohydrate (AM) and aripiprazole lauroxil (AL), remain off-label in the pediatric population. Despite the lack of LAI antipsychotics approved for treatment in youth, the American Academy of Child and Adolescent Psychiatry recommends their use in children and adolescents who have chronic psychotic symptoms and history of poor medication adherence (McClellan et al., 2013). Anecdotal evidence also supports the clinical utility of LAI antipsychotics in youth with other psychiatric conditions, including affective disorders and neurodevelopmental disorders (Benarous et al., 2022b).

A retrospective analysis of a state Medicaid program showed that AM LAI was the third most frequently billed LAI antipsychotic for pediatric patients (n = 150) over a 2-year time period (Modesitt et al., 2018). However, AM LAI became available 8 months after the start of the study, which likely contributed to its lower use. In a 3-year observational study of 30 adolescent inpatients with a range of psychiatric disorders, AM LAI was the most commonly prescribed LAI with the least reported adverse effects (Fortea et al., 2018).

There are also four published case reports that describe good clinical response and tolerability of LAI aripiprazole in youth with psychotic disorders and history of nonadherence. Pope and Zaraa (2016) identified a case in which AM LAI was prescribed for a 15-year-old inpatient male with a primary diagnosis of schizophrenia, who showed improvement in illness severity upon discharge. In Akram and Mitchell's study (2019), AM LAI was safely initiated with a 14-day oral overlap in the setting of CYP2D6 interactions in a 12-year-old male with intellectual disability and psychosis. Aggarwal and Lindegaard (2021) demonstrated that LAI aripiprazole (formulation not specified) delayed time to reincarceration in a 15-year-old male with schizophrenia and conduct disorder. Furthermore, a recent case report from Europe illustrated a two-injection start of AM LAI in a 16-year-old inpatient male with schizophrenia, who was observed to have improved global functioning and insight after 1 month (Salvi et al., 2022).

To date, there have been no reported studies on the use of AL LAI in youth. One advantage of AL LAI is that it allows for initiation through the 1-day oral overlap method, through which patients receive a single oral dose of aripiprazole 30 mg in addition to a single 675 mg injection of the nanocrystal dispersion with the first injection of AL. Therefore, the aim of this retrospective case series is to describe initiation of AL LAI in hospitalized adolescents while examining tolerability and readmission trends.

Methods

This study was based on a 12-bed inpatient adolescent unit at a county-based psychiatric hospital and was approved by the site's Institutional Review Board. Patients 13 to 17 years of age were included if they were initiated on AL LAI between March 2021 and March 2023. Adolescents with medication orders for the nanocrystal dispersion 675 mg injection were identified through a pharmacovigilance platform, VigiLanz. Patient data were collected retrospectively from electronic health records (EHRs) to examine sociodemographic and clinical characteristics during the time of admission requiring AL LAI initiation. Elements included age, sex, psychiatric diagnoses, AL LAI dose and oral overlap, concomitant psychotropics, and length of stay. Information on prior antipsychotic use, adherence history, adverse events (AEs) from AL LAI, and trends in admissions pre- and post-AL LAI was also retrieved through EHR.

Results

Patient characteristics

Twelve adolescents were identified to have initiated treatment with AL LAI. The mean age was 16 ± 1 years, and seven (58%) patients were female. More than half (58%) were of Hispanic background; four patients (33%) were Black and one (8%) was White. None of the adolescents was in foster care. As for primary psychiatric diagnoses, there were three (25%) patients with bipolar disorder, two (17%) with schizophrenia, two (17%) with major depressive disorder (MDD) with psychotic features, two (17%) with unspecified mood disorder, one (8%) with severe mood disorder with psychotic features, one (8%) with intermittent explosive disorder (IED), and one (8%) with disruptive mood dysregulation disorder (DMDD). A third of the patients had a history of cannabis use. Of the 12 adolescents, all except one had trialed at least one antipsychotic before admission with more than half (58%) having prior exposure to oral aripiprazole.

Two patients had a history of receiving monthly intramuscular paliperidone palmitate (PP) LAI. Most patients (83%) were prescribed concomitant psychiatric medications, with the most common being antidepressants (42%), followed by mood stabilizers (17%), alpha-2 agonists (17%), hypnotics (17%), and a stimulant (8%).

AL LAI initiation

For all 12 patients, the first dose of AL LAI was administered on the same day they received the nanocrystal dispersion 675 mg injection. The majority (75%) of patients were initiated on the 441 mg dose; one patient received 662 mg and two patients received 882 mg. Two-thirds of the patients received oral aripiprazole 30 mg for the 1-day overlap; two patients received lower doses and two did not receive oral overlap due to medication refusal. History of medication nonadherence was the main reason for initiating AL LAI in all but one patient, who received the LAI for improved prognosis in schizophrenia.

AL LAI tolerability

As for AE, one patient complained of injection site pain after AL LAI administration. One patient reported experiencing akathisia after receiving one dose of oral aripiprazole during admission but denied any AE from AL LAI. One patient discontinued maintenance treatment with AL LAI 2 months after discharge due to complaint of anxiety.

Admission trends

The length of hospitalization ranged from 2 to 13 days with a mean of 7 ± 4 days; more than half (58%) of the patients were admitted for a time period between 4 to 7 days. Four of the 12 patients had been hospitalized in the preceding 3 months, including three with admissions in the previous month. After AL LAI administration, two patients were readmitted in the next month and one patient within a 3-month time period. Days to readmission ranged from 15 to 658 days for seven patients who had record of rehospitalization.

Refer to Table 1 for a summary of clinical and sociodemographic characteristics.

Table 1.

Clinical and Sociodemographic Characteristics (n = 12)

	Frequency (%) or mean (±SD)
Age (years)	16 (±1)
Sex (females)	7 (58)
Ethnicity
Hispanic	7 (58)
Black	4 (33)
White	1 (8)
Primary psychiatric diagnosis
Bipolar disorder	3 (25)
Schizophrenia	2 (17)
MDD with psychotic features	2 (17)
Unspecified mood disorder	2 (17)
Severe mood disorder with psychotic features	1 (8)
IED	1 (8)
DMDD	1 (8)
Marijuana use	4 (33)
History of nonadherence	11 (92)
Prior oral antipsychotic exposure, at least one	11 (92)
Aripiprazole	7 (58)
Risperidone	6 (50)
Olanzapine	2 (17)
Quetiapine	2 (17)
Lurasidone	1 (8)
Prior LAI exposure (i.e., monthly IM paliperidone palmitate)	2 (17)
Dose of AL LAI initiated
441 mg	9 (75)
662 mg	1 (8)
882 mg	2 (17)
Oral aripiprazole for 1-day overlap
30 mg	8 (67)
20 mg	1 (8)
15 mg	1 (8)
None	2 (17)
Concurrent psychotropic	10 (83)
Antidepressant	5 (42)
Mood stabilizer	2 (17)
Alpha-2 agonist	2 (17)
Hypnotic (specifically trazodone)	2 (17)
Stimulant	1 (8)
Adverse events from AL LAI during admission
Injection site pain	1 (8)
Length of hospitalization (days)	7 (±4)
1–3	2 (17)
4–7	7 (58)
8–14	3 (25)
Record of readmission	7 (58)
Time to readmission
<1 month	2 (17)
>1 and <3 months	1 (8)
>3 and <6 months	1 (8)
>6 months and <1 year	1 (8)
>1 year	2 (17)

AL, aripiprazole lauroxil; DMDD, disruptive mood dysregulation disorder; IED, intermittent explosive disorder; IM, intramuscular; LAI, long-acting injectable; MDD, major depressive disorder; SD, standard deviation.

Cases

Patient 1

A 16-year-old Hispanic male with no prior psychiatric hospitalization was admitted for nontargeted violent thoughts, paranoia, and auditory and visual hallucinations. His psychiatric history was unclear, but family reported that the patient had taken bupropion in the past for “concentration.” He was diagnosed with early-onset schizophrenia and initiated on oral aripiprazole, which was titrated for 6 days to 10 mg. He was then transitioned to AL LAI 441 mg given “improved prognosis with consistent treatment in psychotic illness.” In the following month, he received his maintenance dose from an outpatient provider, but the LAI was discontinued thereafter due to complaint of anxiety.

Patient 2

A 15-year-old Hispanic male with IED and unspecified mood disorder was admitted for suicidality and self-harm behavior. He had been nonadherent to aripiprazole and divalproex sodium for 2 weeks, leading to increased irritability and frequent anger outbursts. He also had an extensive record of psychotropic use and history of numerous hospitalizations. The patient was restarted on oral aripiprazole 20 mg and converted to AL LAI 882 mg. Two months after discharge, the patient visited emergency treatment services (ETS) as his outpatient psychiatrist did not prescribe LAIs to minors. AL LAI was reinitiated during the encounter as family described significant symptomatic improvement with the LAI and continued nonadherence to oral medications. The patient was readmitted 25 days later due to AL LAI “wearing off” and received his maintenance dose during hospitalization.

Patient 3

A 17-year-old Hispanic female with MDD with psychotic features and concern for prodromal schizophrenia was hospitalized for a suicide attempt by hanging. According to family, the patient exhibited signs of depression and erratic, bizarre behavior after her brother, who had a diagnosis of schizophrenia, died by suicide. She was restarted on her prior psychopharmacologic regimen of aripiprazole 5 mg and escitalopram 10 mg, to which she had been nonadherent for 2 weeks. The patient continued to refuse medications during admission, which supported initiation of AL LAI 441 mg. In the outpatient setting, the patient was reinitiated on AL LAI after 10 months.

Patient 4

A 15-year-old Black male with severe mood disorder with psychotic features was admitted for suicidal ideation with worsening auditory hallucinations and paranoid delusions. His urine drug screen (UDS) was positive for tetrahydrocannabinol (THC), but family endorsed psychotic symptoms outside of cannabis use. In his previous hospitalization, he was discharged on oral aripiprazole but was unable to fill the prescription and had not taken any medication for several months, leading to decompensation. The patient was started on AL LAI 662 mg after establishing tolerance to oral aripiprazole of up to 15 mg. A month after discharge, the patient presented to ETS as his outpatient provider did not supply LAIs to minors. His mother reported improvement in mood and resolution of psychotic symptoms with AL LAI, so the patient was given his maintenance dose during the encounter.

Patient 5

A 15-year-old White female with bipolar disorder, bulimia nervosa, and cannabis use disorder was hospitalized for suicidal ideation and self-harm behavior. She had recently been admitted for a suicide attempt that required medical treatment for bilateral wrist fractures after attempting to jump off a bridge. Her self-injurious behavior was thought to be likely related in part to her mother's diagnosis of terminal cancer. Her home medication aripiprazole was titrated to 10 mg; mirtazapine and clonidine were initiated as well. Given her history of nonadherence and medication refusal during hospitalization, the patient was transitioned to AL LAI 441 mg. Although the patient reported experiencing akathisia after one dose of oral aripiprazole 10 mg, she denied any AE after receiving the LAI. A couple of days following discharge, the patient was readmitted for “running away from home and threatening to hurt herself.” She was subsequently hospitalized a week later for similar presentation.

Patient 6

A 14-year-old Hispanic female with MDD with psychotic features was admitted for a suicide attempt by ligature strangulation. Her prior psychopharmacologic regimen consisted of risperidone and sertraline, but the patient stopped taking risperidone for 3 days due to severe headaches that did not subside for 2 weeks. Risperidone was thus switched to aripiprazole, which was titrated for 5 days to 10 mg. The patient was converted to AL LAI 441 mg without any notable AE. Eleven days after discharge, she was readmitted for suicidality, prompting lithium to be added to her regimen. She also received oral paliperidone with plan to transition to PP LAI due to concern of poor response to AL LAI.

Patient 7

A 15-year-old Hispanic female with bipolar disorder, IED, generalized anxiety disorder and social anxiety disorder was hospitalized for suicidal ideation with intent to overdose. The patient displayed worsening mood, irritability, and aggression in the setting of nonadherence to aripiprazole and clonidine for 1 month. Her UDS was also positive for THC. It was noted that the patient was previously on risperidone but stopped taking the medication due to galactorrhea. She was restarted on oral aripiprazole 10 mg and transitioned to AL LAI 441 mg.

Patient 8

A 17-year-old Hispanic female with a 3-year history of schizophrenia was admitted for psychotic decompensation leading to impulsivity, verbal aggression, and physical violence. She was previously on PP LAI but had not received it for >1 year. Risperidone was started during hospitalization, but the patient refused the medication due to prior AE of gynecomastia. Risperidone was thus switched to aripiprazole, and the patient received AL LAI 882 mg due to concern for nonadherence.

Patient 9

A 17-year-old Black female with autism spectrum disorder, attention-deficit/hyperactivity disorder (ADHD), unspecified mood disorder, and borderline personality disorder was admitted for suicidal ideation with self-harm behavior and plan to overdose. Her prior psychopharmacologic regimen comprised sertraline, lithium, and dextroamphetamine/amphetamine extended release (XR). She had also trialed oral risperidone and PP LAI in the past, which were beneficial for symptoms but led to weight gain. Her mother requested for an LAI antipsychotic due to history of poor adherence, so the patient received AL LAI 441 mg after establishing tolerability to oral aripiprazole 10 mg. As for other psychotropics, dextroamphetamine/amphetamine XR was resumed, sertraline was optimized, and lithium was tapered off due to inefficacy and concern for overdose.

Patient 10

A 16-year-old Hispanic male with a history of ADHD, intellectual disability (ID), unspecified anxiety disorder and unspecified disruptive, impulse-control, and conduct disorder was admitted for suicidal intent and physical aggression. He was diagnosed with DMDD and MDD during hospitalization. Family reported that the patient had responded well to treatment with escitalopram and aripiprazole but was nonadherent to the regimen for 1 month. He was thus restarted on escitalopram in addition to being initiated on AL LAI 441 mg; he did not receive oral aripiprazole due to known history of tolerance and response to dose of 10 mg. In the outpatient setting, the patient continued to receive maintenance doses of AL LAI 441 mg and tolerated it well for >2 years.

Patient 11

A 16-year-old Black female with bipolar 1 disorder with psychosis was hospitalized for physical and verbal aggression in the setting of command hallucinations to hurt herself and others. She had not taken divalproex sodium and olanzapine for 3 months due to AE of sedation and weight gain. She also endorsed use of THC, alcohol, and lysergic acid diethylamide. Olanzapine was changed to aripiprazole, which was titrated for 1 week to 10 mg. She was subsequently converted to AL LAI 441 mg. The patient continued to receive maintenance doses for >1.5 years in the outpatient setting.

Patient 12

A 17-year-old Black male with ID, unspecified mood disorder and unspecified disruptive, impulse-control, and conduct disorder was admitted for physical aggression and threatening behavior toward his mother. The patient was restarted on his prior psychopharmacologic regimen of aripiprazole 10 mg but refused the medication during hospitalization. He was eventually transitioned to AL LAI 441 mg due to poor medication adherence. The LAI was discontinued in the outpatient setting for an unspecified reason.

Refer to Table 2 for individual patient profiles.

Table 2.

Patient Profiles

ID	Age	Sex	Discharge diagnoses	LOS	New start OA	OA OL dose	AL LAI dose	Concomitant medication(s)	Total no. past admissions	No. of past admission(s) within 1 month; 3 months	No. of readmission(s) at 1 month; 3 months	Days to 1st readmission
1	16	Male	Schizophrenia (1°)	6	Yes	30	441	Trazodone 50 mg qHS PRN insomnia	0	0;0	0;0	n/a
2	15	Male	IED (1°) Unspecified mood disorder	2	No	30	882	Divalproex sodium 750 mg qHS	16	0;0	0;1	81
3	17	Female	MDD with psychotic features (1°)	12	No	None	441	Escitalopram 10 mg daily	2	2;2	0;0	255
4	15	Male	Severe mood disorder with psychotic features (1°)	5	No	30	662	None	3	0;0	0;0	n/a
5	15	Female	Bipolar disorder (1°) Bulimia nervosa Cannabis use disorder	13	No	20	441	Mirtazapine 7.5 mg qHS Clonidine 0.1 mg daily	3	0;2	2;2	15
6	14	Female	MDD with psychotic features (1°)	7	Yes	15	441	Sertraline 50 mg daily	1	1;1	1;1	18
7	15	Female	Bipolar disorder (1°) IED GAD SAD	3	No	30	441	Clonidine 0.2 mg daily	2	0;0	0;0	n/a
8	17	Female	Schizophrenia (1°)	4	Yes	30	882	None	2	0;0	0;0	570
9	17	Female	Unspecified mood disorder (1°) Borderline personality disorder ADHD ASD	6	Yes	30	441	Sertraline 75 mg daily Dextroamphetamine/amphetamine XR 20 mg daily	9	1;2	0;0	n/a
10	16	Male	DMDD (1°) MDD	4	No	None	441	Escitalopram 10 mg daily	4	0;0	0;0	n/a
11	16	Female	Bipolar 1 disorder with psychosis (1°)	13	Yes	30	441	Divalproex sodium 1000 mg qHS Trazodone 150 mg qHS Melatonin 5 mg qHS	1	0;0	0;0	658
12	17	Male	Unspecified mood disorder (1°) Unspecified disruptive, impulse-control, and conduct disorder ID	4	No	30	441	None	4	0;0	0;0	94

1°, primary; ADHD, attention-deficit/hyperactivity disorder; AL LAI, aripiprazole lauroxil long-acting injectable; ASD, autism spectrum disorder; DMDD, disruptive mood dysregulation disorder; GAD, generalized anxiety disorder; ID, intellectual disability; IED, intermittent explosive disorder; LOS, length of stay; MDD, major depressive disorder; n/a, not applicable; OA, oral aripiprazole; OL, overlap; PRN, as needed; qHS, every night at bedtime; SAD, social anxiety disorder; XR, extended release.

Discussion

Of the 12 adolescents initiated on AL LAI, half had a primary diagnosis associated with psychotic symptoms. The majority (58%) of patients received AL LAI due to poor adherence to oral aripiprazole before admission. A third of the patients were switched to aripiprazole from a different antipsychotic with poor tolerability and transitioned to AL LAI due to history of medication nonadherence. One adolescent with no prior history of antipsychotic use was newly initiated on oral aripiprazole and converted to AL LAI for improved prognosis. In two patient cases, family reported improvement in symptoms after initiation of AL LAI and requested maintenance doses in ETS. Moreover, two other patients were confirmed to continue treatment with AL LAI for >1 year. Three patients discontinued AL LAI after discharge; one was due to concern for inefficacy, one due to anxiety, and one for an unknown reason.

The cases presented in this study illustrate that AL LAI may hold potential as an effective and acceptably tolerated treatment option in adolescents with a range of psychiatric conditions, including psychotic and mood disorders. As observed in our case series, nonadherence to antipsychotics is prevalent in adolescents (Benarous et al., 2022a; Pogge et al., 2005). This is a clinically relevant issue as poor medication adherence in youth with severe mood or psychotic disorders is associated with greater morbidity and incidence of readmission (Benarous et al., 2022a; Edgcomb and Zima, 2018; Fontanella, 2008).

Literature has demonstrated several benefits of LAI antipsychotics in adults, including lower risk of relapse and hospitalization in addition to improved adherence and functionality (Brissos et al., 2014; Kaplan et al., 2013; Kishimoto et al., 2018; Leucht et al., 2011). Although data focused on LAI treatment in pediatrics is scarce, reviews of literature suggest that their use in youth with serious mental illness may improve clinical outcomes with better or similar safety profiles to oral formulations (Baeza et al., 2023; Benarous et al., 2022a; Lytle et al., 2017).

Limitations of this study include the retrospective design and small sample size. CYP2D6 phenotypes were not known. Long-term outcomes were beyond the scope of this study. Nevertheless, to the authors' knowledge, this is the first case series to highlight initiation of AL LAI in pediatric patients. Moreover, this study describes the use of AL LAI for adolescents with varying psychiatric diagnoses. As depicted in two of our patient cases, reluctance of providers to prescribe LAIs off-label for youth hindered continuation of treatment after hospitalization despite positive response to AL LAI. Therefore, it is imperative to conduct more studies on the use of LAIs in youth to better examine their role in treating psychiatric disorders in this population.

Conclusion

This case series describes AL LAI initiation in hospitalized adolescents, including short-term tolerability and readmission trends. The observations from this study suggest that AL LAI may be a safe treatment option in youth with varying psychiatric conditions who require an antipsychotic agent and are at risk of medication nonadherence.

Clinical Significance

This study aims to address the gap in literature regarding LAI treatment for adolescents and to provide insight into current clinical practice. This is the first study to report findings on the use of AL LAI in youth. Our cases highlight initiation of AL LAI doses up to 882 mg without significant concerns for tolerability. In a few patients, the oral overlap dose was not given or lower than what is recommended in adults. More studies are necessary to determine the most appropriate overlap method in youth. Given the lack of approved LAI antipsychotics for the pediatric population, reports on the clinical utility of these agents in children and adolescents are important. Further research on the long-term efficacy and safety of AL LAI in addition to other LAIs in youth is needed.

Footnotes

Disclosures

No competing financial interests exist.

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