Long-Acting Injectable Atypical Antipsychotic Use in Adolescents: An Observational Study

Abstract

Objectives:

Although second generation long-acting injectable antipsychotics (SG-LAIAs) have been approved and are widely used in adults, there is limited evidence for the use of long-acting formulations in children and adolescents. Thus, we systematically describe the off-label use of SG-LAIAs in clinical practice in adolescent inpatients.

Methods:

All individuals admitted to our Children and Adolescent Inpatient Psychiatry Unit receiving treatment with SG-LAIAs between January 2013 and June 2016 were reviewed. A retrospective analysis of medical records was conducted. Clinical diagnoses were established using DSM-5 criteria.

Results:

Thirty individuals (53.3% female) out of a total of 1,148 admitted patients (2.6%) were identified. The mean age was 16.3 (SD = 1.3; range: 12.5–17.9).The main diagnoses were psychosis (70%) and disruptive behavior disorders (DBDs) (30%), although comorbidity was frequent (96.6%), especially drug use (55.2%, mostly cannabis). SG-LAIAs used were aripiprazole (40%), risperidone (36.7%), and paliperidone palmitate (23.3%), and the main reasons were a history of low compliance (90%) and/or poor insight (73.3%). A mean improvement of 31.7 (SD = 8.7) between admission and discharge was registered in the Children's Global Assessment Scale (CGAS); no differences were observed between different SG-LAIAs. Although they were generally well tolerated, 23.3% of patients reported mild short-term side effects, which were more frequent with risperidone than with aripiprazole (p = .014).

Conclusions:

Our clinical experience suggests that SG-LAIAs may be a safe treatment option during adolescence in inpatients with psychotic disorders, as well as with DBD. No differences were found in CGAS improvement scores between the three SGA-LAIAs used, although patients on risperidone reported more side effects than those on aripiprazole. Further research is needed so as to evaluate safety and effectiveness of SG-LAIAs in this population.

Introduction

Oral antipsychotics are used for the treatment of several psychiatric disorders in children and adolescents (Correll et al. 2011). Oral paliperidone extended release and aripiprazole have demonstrated efficacy in adolescents in the treatment of schizophrenia (Singh et al. 2011; Diomšina et al. 2015; Savitz et al. 2015). Furthermore, in child and adolescent population, off-label use of oral antipsychotics in daily practice is documented for psychotic disorders, in addition to affective disorders, disruptive behavior disorders (DBDs), eating disorders, attention-deficit/hyperactivity disorder, autism spectrum disorders, and Tourette's syndrome (Winterfeld et al. 2008; Baeza et al. 2014; Schneider et al. 2014).

Second generation long-acting injectable antipsychotics (SG-LAIAs) have been approved as a valid treatment strategy for schizophrenia in adults (Citrome 2013; NICE 2014). There is growing evidence that long-acting injectable antipsychotics (LAIAs) are associated with higher quality of life and functionality, better prognosis, and reduced risk of relapse compared with oral formulations (Leucht et al. 2011; Kaplan et al. 2013; Kishimoto et al. 2013; Brissos et al. 2014). However, LAIAs are not currently approved for use in youth under the age of 18, despite evidence that many mental health disorders have their onset during childhood or adolescence (Driver et al. 2013). Nevertheless, the American Academy of Child and Adolescent Psychiatry has stated that LAIAs should be considered in patients with schizophrenia with chronic psychotic symptoms and a history of poor medication adherence (McClellan and Stock 2013).

Poor compliance in the early stages of psychosis and bipolar spectrum disorder may lead to a longer duration of untreated illness. This can have an impact on the clinical, functional, and psychosocial decline that occurs within the first years after onset and has been associated with greater illness-related changes in the brain (Crumlish et al. 2009; Puri 2010; Emsley et al. 2013; Medeiros et al. 2016). Furthermore, in adolescence factors associated with poor compliance such as comorbid drug use and poor insight may be more prevalent (Parellada et al. 2011). This has led to increased interest in the role of SG-LAIAs in youth, with some experts suggesting that they should be used earlier and more frequently in this age group (Parellada et al. 2012; Lachman 2014).

There is limited evidence for the use of LAIAs in children and adolescents (Erermis et al. 2007; Fu-I et al. 2009; Wisniewski 2011; Boarati et al. 2013; Patel et al. 2013). Apart from risperidone long-acting injection, few case reports have focused on new SG-LAIAs such as paliperidone palmitate or aripiprazole (Kowalski et al. 2011; Fàbrega et al. 2015; Pope and Zaraa 2016). Lytle et al. (2017) recently conducted a literature review that identified 7 articles, collectively encompassing 36 individuals, which suggested that the use of LAIAs in youth with severe mental disease could improve clinical outcomes and adherence with similar side effects to oral preparations. However, they also highlighted the need for more research assessing safety and effectiveness of SG-LAIAs in this age group.

We set out to provide a clinical description of a sample of adolescent patients in whom off-label treatment with SG-LAIAs was initiated during inpatient admission.

Methods

This study was approved by the ethics committee in our hospital. All patients admitted between January 2013 and June 2016 in the child and adolescent acute psychiatric ward of Hospital Clinic de Barcelona were systematically reviewed. All patients starting treatment with SG-LAIAs during the period of hospitalization were included. Sociodemographic and clinical data were retrospectively collected by their treating physician from computerized charts and then transferred to an anonymized data base to conduct the analyses, following procedures recommended by the ethics review board of our center for retrospective studies. Medical history and mental state examinations recorded by clinicians were used to register reasons for referral, previous compliance, and insight for each subject. Global functioning was evaluated with the Children's Global Assessment Scale (CGAS), which is a widely used tool derived from the Global Assessment Scale and adapted for use in children and adolescents to assess overall level of functioning (Shaffer et al. 1983). This rating is systematically recorded for every hospitalized patient and is measured at the time of admission and discharge. Two patients were discharged without having completed the transition between oral and LAIA (risperidone and paliperidone); to facilitate the interpretation of the results, the oral prescription at discharge for these two patients was not considered in the statistical analysis. The descriptive statistical analysis was conducted in Stata IC 13.1, using Wilcoxon test for quantitative data and exact Fisher test for qualitative variables. A post-hoc analysis was performed comparing outcomes according to drug misuse and main diagnosis.

Results

Participants' characteristics

From 1,148 patients admitted during 3.5 years, 33 subjects were identified as receiving treatment with SG-LAIAs. Three subjects were excluded given that SG-LAIAs had been introduced before hospital admission. Therefore 30 (2.6%) patients were finally included (14 males and 16 female) with an average age of 16.3 years (SD = 1.3; range: 12.4–17.9) at admission (Table 1 for more detailed sociodemographics). Psychotic disorder was the most frequent diagnosis, as seen in Table 1, and drug misuse (especially cannabis) was the most common comorbidity. In fact, most of the patients (93.3%) presented comorbidities (mean number of comorbid diagnoses was 2; range: 1–4). Five patients had an intellectual disability and four had a borderline intelligence quotient.

Table 1.

Clinical and Sociodemographic Characteristics of the Sample According to Type of Second Generation Long-Acting Injectable Antipsychotic

	Risperidone LAI (n = 11)	Paliperidone LAI (n = 7)	Aripiprazole LAI (n = 12)	p
Age (years)	16.0 (SD = 1.3)	16.5 (SD = 1.4)	16.4 (SD = 1.4)	0.52
Sex (females), n (%)	45.5	42.9	66.7	0.52
Foster care, n (%)	27	0	33	0.27
Prior antipsychotic exposure
Risperidone, n (%)	54	71	67	>0.23
Aripiprazole, n (%)	36	71	50
Olanzapine, n (%)	36	43	25
Quetiapine, n (%)	36	14	25
Paliperidone, n (%)	0	14	8
Others, n (%)	Haloperidol (9)	Clozapine (14)
	Fluphenazine (9)	Levomepromazine (14)
Diagnosis
Psychotic disorder, n (%)	73	86	58	>0.17
Disrupted behavior disorder, n (%)	45	43	75
Attention deficit/hyperactivity disorder, n (%)	45	29	50
Affective disorder, n (%)	27	0	42
Intellectual disability, n (%)	18	14	17
Autism spectrum disorder, n (%)	9	0	8
Cannabis misuse, n (%)	40	86	50	0.21
Range of dose of LAI	25–50 mg	50–150 mg	300–400 mg	—
Concurrent oral antipsychotics	18%	14%	25%	1.0
	Clotiapine (n = 1)	Clotiapine (n = 1)	Olanzapine (n = 1)
	Risperidone (n = 1)		Quetiapine (n = 2)
Concurrent ADHD medication (methylphenidate, atomoxetine), n (%)	18	0	0	0.18
Concurrent mood stabilizer (Valproic acid, lithium), n (%)	18	29	33	0.87
Concurrent antidepressants (Fluoxetine), n (%)	0	0	17	0.33
Adverse side effects, n (%)	45	29	0	0.02^a
	Hyperprolactinemia (n = 3)	Hyperprolactinemia (n = 1)
	Sedation (n = 1)	Akathisia (n = 1)
	Dystonia (n = 1)
Hospitalization (days)	20 (SD = 11)	22 (SD = 9)	13 (SD = 4)	0.08
CGAS (difference between admission and discharge)	+33 (SD = 9)	+29 (SD = 9)	+33(SD = 9)	0.94

Post-hoc, only significant for Aripiprazole >Risperidone (p = 0.014). Reported for all range of doses.

CGAS, Children's Global Assessment Scale; LAI, long-acting injection; SD, standard deviation.

Fifty-seven percent of the subjects had had previous admissions (median: 1; range: 1–6). Reasons for current admission were aggression (76.7%), delusions (50.0%), bizarre behavior (43.3%), negative symptoms (36.7%), hallucinations (30%), depressive symptoms (20%), and/or suicidal thoughts (20%). Almost two-thirds of adolescents were not attending school before admission (7 sporadically and 12 presented total absenteeism). (See Supplementary Data; Supplementary Data are available online at www.liebertpub.com/cap)

Treatment and reasons for introduction

Twenty-nine patients switched from oral antipsychotic medication to SG-LAIAs, and one patient switched from intramuscular fluphenazine to risperidone. The median of previously trialed antipsychotic agents was two (range: 1–5), see Table 1 for more details. Twelve subjects started aripiprazole (dose range: 300–400 mg), 11 risperidone (dose range: 25–50 mg), and 7 paliperidone palmitate (dose range: 50–150 mg) (Table 1), mainly due to low treatment compliance (90%) and poor insight (73.3%). Poor insight was reported for all cases, and the majority had either entirely abandoned (15 out of 27) treatment before admission or had presented irregular adherence (12 out of 27). Other reasons for SG-LAIA introduction included no supervision (30%) and treatment refusal (6.7%). Concurrent medication is detailed in Table 1, showing no differences in pre- and post-antipsychotic co-medication (12% vs 16%; p = 0.66). There was only one patient receiving the same drug orally and in long-acting formulation who was suspected to be an ultrarapid metabolizer. Table 2 shows that there were significant differences in the rates of antidepressant treatment between admission and discharge, which decreased from 24% to 8% (p = 0.043).

Table 2.

Concurrent Medication at Admission and After Starting Treatment with Second Generation Long-Acting Injectable Antipsychotics (n = 25)

	At admission, n (%)	Post- SG-LAIAs, n (%)	p (t-test)
Concurrent oral antipsychotics	12	16	0.66
ADHD medication	12	8	0.32
Mood stabilizers	28	28	1.0
Antidepressants	24	8	0.04

Adolescents who were not in pharmacological treatment at admission were excluded from the analysis.

SG-LAIAs, second generation long-acting injectable antipsychotics; ADHD, attention-deficit/hyperactivity disorder.

Clinical outcomes and reported adverse effects

CGAS improved significantly (p < 0.001) in 32 points (SD = 9) between admission and discharge, with no differences between SG-LAIAs (Table 1). Less than a quarter of subjects reported adverse side effects, among which hyperprolactinemia was the most prevalent (detailed in Table 1) and was significantly higher in risperidone than with aripiprazole (p = 0.014), although adverse effects led to no discontinuation of treatment. There were no differences in reported adverse effects between those receiving concurrent oral antipsychotic and those who did not (p = 0.12).

Family history

Four adolescents were adopted, 7 were in foster care, in 21 cases parents were separated or divorced, and in 8 cases these conditions were combined (5 in foster care with divorced parents, 2 adopted with divorced parents, and 1 adopted and in foster care). Family history was available for 27 subjects, and 88.9% had at least one relative with mental health problems: mainly psychosis (44.0%; n = 25), drug misuse (29.6%), and/or affective disorder (29.6%).

Differences by diagnosis

In a secondary exploratory analysis dividing the sample by drug misuse we found no significant differences between patients with and without cannabis use, except for the fact that cannabis users were older (p = 0.003). Dividing the sample by main diagnosis, those with psychotic disorders had longer admissions (p = 0.017); no further differences were observed in any other clinical or treatment related factors.

Discussion

This retrospective study describing clinical practice in an inpatient unit involving 30 patients showed that treatment with SG-LAIAs is a relevant choice for clinicians when it comes to adolescent patients. In our sample, aripiprazole was the most common SG-LAIA used and the one with least reported side effects. Lack of insight and previous history of poor treatment adherence were the main reasons for initiating SG-LAIAs.

Treatment

The most frequently prescribed SG-LAIA was aripiprazole (n = 12; 40%)—even though it has only been available in our country since February 2015—followed by risperidone (n = 11; 36.7%) and paliperidone palmitate (n = 7; 23.3%), available from 2003 and 2011, respectively. In our sample, there were no differences in CGAS improvement, between the three medications. Although we found a trend-level shorter hospitalization in the aripiprazole group, this should not be interpreted in terms of effectiveness, since it could have been driven by differences in diagnosis or symptom severity that may have influenced the prescriber's choice. Nevertheless, patients receiving aripiprazole showed less adverse effects compared to risperidone. Previous reports on SG-LAIAs in children and adolescents have focused on risperidone (n = 24) and paliperidone palmitate (n = 8) (Lytle et al. 2017); in the literature aripiprazole long-acting injection (ALAI) was only prescribed in one occasion due to previous bad tolerability to risperidone (Pope and Zaraa 2016). This may be the consequence of a lengthier clinical experience with risperidone versus other SG-LAIAs. Thus, in coming years we expect a change in this tendency, with a boost in the use of aripiprazole, which appears to have a better adverse reaction profile (Kumar et al. 2013), and paliperidone palmitate, which has longer lasting formulations (Bernardo and Bioque 2016).

Reason for introduction

In our sample, all patients showed scarce insight and were therefore at risk of treatment discontinuation. Indeed, 90% of individuals either had a history of irregular adherence or had already interrupted previous oral treatment, which was the main reason for introducing SG-LAIAs. Lack of insight, which refers to unawareness of having a mental disorder and of the need of treatment, is a common clinical characteristic of psychotic disorders (Amador et al. 1993). Worse insight has been related to more severe symptoms, increased risk of discontinuing treatment, and poorer outcomes (Cuesta and Peralta 1994; Osatuke et al. 2008). In addition, it has been suggested that younger patients, especially adolescents with schizophrenia spectrum disorders, may have less insight than their adult counterparts (McEvoy et al. 2006; Parellada et al. 2009, 2011).

Children, and particularly adolescents, have been reported to have higher risk for nonadherence (Hack and Chow 2001). Other conditions such as substance abuse, violence, or legal conflicts are also risk factors for lack of compliance (Zhornitsky and Stip 2012; Czobor et al. 2015; Parellada and Bioque 2016). Related to this, we found that 76.7% presented with aggressive behavior, 53.2% used cannabis, and 23.3% were in foster care.

Evidence from adult samples suggests that SG-LAIAs may improve treatment adherence and secondarily reduce the risk of relapse (Zhornitsky and Stip 2012), which is an important cause of loss of functionality and worse clinical outcomes (Norman and Malla 2002; Czobor et al. 2015). Thus, SG-LAIAs may therefore reduce the risk of relapse in adolescents and improve their long-term outcomes, although this will need to be demonstrated with a longitudinal design.

Clinical outcome

Our results suggest a significant improvement in CGAS scores, with no differences according to the type of SG-LAIA. Studies so far have shown decreased positive and negative symptoms and improved social functioning, measured with the CGAS and CGI-S (Clinical Global Impressions Severity of illness Scale), in patients with schizophrenia receiving SG-LAIAs (reviewed in Lytle et al. 2017). One previous study reported a maintained effect of this improvement in the CGAS at 6 months after starting risperidone (Boarati et al. 2013), which is the longest follow-up reported in the literature in a pediatric population.

Tolerability and adverse effects

SG-LAIAs were generally well tolerated during the first days and weeks of treatment. Nevertheless, as expected, 21% reported mild side effects, similar to those described for oral formulations (Correll 2008).

In our study there was a significant reduction in the use of antidepressants, which contrasts with reports of an increased average of psychotropic medications from hospital admission to discharge (Pappadopulos et al. 2002; Dean et al. 2006). In our sample antidepressant medication was stopped in four cases: three when switching from oral to long-acting aripiprazole and one from oral olanzapine to long-acting risperidone. Although the introduction of SG-LAIAs could have exerted a role, the precise reason for antidepressant withdrawal is uncertain, and hospitalization itself may have also played a part. Overall, this may support the hypothesis than long-term formulations are likely to help reduce prescription of other psychotropic drugs.

Diagnosis

Despite the fact that the majority of individuals in our study were diagnosed with psychotic disorders (70%), in a substantial proportion of our sample (n = 9, 30%), DBD was the primary diagnosis. To our knowledge, there is only one published case report that successfully treated an adolescent with conduct disorder with long-acting risperidone (Tutkunkardas and Abali 2011), although oral antipsychotic treatment has been well documented in adolescents with conduct disorders (Findling et al. 2006; Baeza et al. 2014; Schneider et al. 2014). Our findings show that there were no significant differences in terms of effectiveness and tolerability between psychotic and DBD patients. Duration of admission was longer in patients with psychosis than with DBD, which is consistent with reports of longer length of stay in adolescent units for patients with psychotic disorders compared to those with other diagnoses such as mood and anxiety disorders (Harman et al. 2004; Hanssen-Bauer et al. 2011).

Limitations and strengths

The main limitations of this study are the reduced sample size, the retrospective design, the lack of a structured diagnostic interview, and the absence of a control group. Nevertheless, to our knowledge this is the largest sample illustrating use of SG-LAIAs in adolescents so far, in which patients with DBD are also represented. Moreover, this study describes the use of long-acting aripiprazole, which has so far been scarcely reported on. Although prospective, randomized controlled trials are needed to fully evaluate short- and long-term safety and effectiveness of SG-LAIAs in child and adolescent population, this observational and naturalistic approach has the advantage of reflecting clinical daily practice.

Conclusion

SG-LAIAs may be a safe option of treatment in adolescent patients who suffer from a range of mental health disorders. Treatment adherence and long-term outcomes may be improved with SG-LAIAs in this vulnerable age group. Although these results should be interpreted with caution given the methodological limitations, our data suggest that clinicians should not only consider SG-LAIAs for patients with schizophrenia with chronic symptoms and history of poor medication adherence—as recommended by the American Academy of Child and Adolescent (McClellan and Stock 2013)—but also as an initial option in adolescents with other psychiatric conditions, which require treatment with an antipsychotic drug and are at risk of low compliance.

Clinical Significance

While evidence is still very limited, this study provides an additional insight into the clinical use of SG-LAIAs in adolescent patients. To our knowledge, this is the largest sample describing clinical and sociodemographic features, together with data on short-term clinical outcome and side effects, in patients starting treatment with SG-LAIAs during hospital admission.

Disclosures

I.B. and G.S. have received honoraria from Otsuka-Lundbeck and Janssen, research support from Fundación Alicia Koplowitz, and grants from the Spanish Ministry of Health, Instituto de Salud Carlos III. D.I. is grant holder from Fundación Alicia Koplowitz. A.F., C.C., M.S., D.I., and G.O. have received honoraria from Lundbeck and Janssen.

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