Adverse Events Associated with Risperidone Use in Pediatric Patients: A Retrospective Biobank Study

Despite relatively narrow US FDA-approved indications in children and adolescents, antipsychotic drugs are important in the treatment of several pediatric conditions, and prescription rates for young people are on the rise [1‐4]. Risperidone, a serotonin-dopamine antagonist, is FDA approved for use in children aged 5–16 years to treat irritability associated with autism, in children aged 10–17 years to treat mania and mixed state due to bipolar disorder, and in children aged 13–17 years to treat schizophrenia [3]. Risperidone is also increasingly used “off-label” for conditions including developmental and disruptive disorders, depression, obsessive-compulsive disorder (OCD), post-traumatic stress disorder, personality disorder, attention-deficit/hyperactivity disorder (ADHD), and Tourette syndrome [4, 5].

Clinically important adverse events (AEs) attributed to risperidone include weight gain, prolonged QTc, tardive and withdrawal dyskinesia, diabetes mellitus, and hyperlipidemia, all of which have been well-documented in adults [6‐8]. The reported incidence of AEs with risperidone, based on limited studies in adults, ranges from 1 in 16 patients to 68 in 100 patients, depending on the population studied and the definition of AEs [9, 10]. According to the American Academy of Child and Adolescent Psychiatry, AEs with atypical antipsychotics in children are similar to those seen in adults [4], but there are concerns that the consequences of risperidone-related AEs may be more serious in children than in adults [6].

There are very limited data documenting the AE profile of risperidone in young patients. Studies published to date have been of small patient cohorts representing specific subgroups of pediatric patients and have focused on the most common AEs such as weight gain and enuresis [7, 10‐16]. Further, the studies were limited to ≤ 8 weeks and were unable to capture the AEs associated with prolonged use of risperidone. There are reports of additional AEs with prolonged use of risperidone, including iron deficiency anemia, pituitary tumors, hyperprolactinemia, low bone mineral density, arterial hypertension, and posterior reversible cerebral edema syndrome [17‐20].

Due to developmental changes in the expression of drug targets, transporters, ion channels, receptors, and downstream signal transduction pathways, AE profiles may differ across age groups [21]. Further, children and adolescents may also be at a greater risk for rare AEs than adults. Because fewer children than adults are treated with most atypical antipsychotic medicines, the data available from passive reporting databases such as the FDA Adverse Event Reporting System (FAERS) are limited, and available information on rare AEs of risperidone may be insufficient to guide rational prescribing for children and adolescents.

In this study, we sought to determine the incidence of and risk factors for AEs among children treated with risperidone at our institution. We used a de-identified electronic health record (EHR)-based data repository to study AEs among 371 children and adolescents exposed to risperidone for at least 4 weeks and, in doing so, also enabled an analysis of risperidone use patterns at this tertiary care children’s hospital.

Risperidone use in our cohort resulted in substantial number of common and rare AEs. On-label versus off-label use was not significantly associated with AE and, after controlling for the significant clinical variables, only self-injurious behavior and concomitant antibiotics were associated with AEs. The odds of AEs were higher in the presence of self-injurious behavior than in children without this indication for risperidone use, and lower with concomitant antibiotics.

Nearly one-third of this study cohort had experienced at least one AE, warranting close monitoring of children and adolescents treated with risperidone. Previous smaller studies involving children and adolescents with prolonged exposure to risperidone have reported higher rates (48–65%) [12, 13, 26], whereas a single study reported a lower rate (28.2%) [27]. Differences in the population studied, the methodology used, the duration of use of risperidone, and sample sizes may underlie the disparate AE rates. Our cohort included children and adolescents with a wide range of psychiatric and non-psychiatric disorders. By contrast, most prior studies of risperidone AEs involved children and adolescents with autism/autism spectrum disorder or disruptive behavior disorders [12, 13, 26, 27]. Our study was retrospective, with AEs detected from EHR documentation, whereas others were prospective, randomized, and double blind or open label, with active monitoring for AEs [12, 13, 26]. While the retrospective nature of our study leads to some limitations, merits of this design are less selection bias than prospective clinical trials and a focus on AEs that were documented by clinicians. Thus, our data may be more representative of “real-world” populations and clinically relevant findings. We also evaluated a larger cohort of 371 individuals, whereas the largest cohort published to date includes ≤172 individuals [13, 26‐29].

Our cohort had a wide range of AEs, including common AEs (e.g., weight gain, extrapyramidal symptoms, and daytime hypersomnia) and rare AEs (e.g., premature adrenarche, precocious puberty, and early menstrual flow). Nearly one-quarter of our patients experienced multiple AEs. Consistent with other studies, common and rare AEs have been reported with risperidone among children and adolescents with autism and disruptive behavioral disorders, and weight gain is one of the most common AEs [12, 13, 26‐29]. Some prior studies had reported respiratory system disorders as common AEs with risperidone (e.g., upper respiratory tract infection, rhinitis, pharyngitis) [12, 13], which we did not identify in our cohort. Respiratory AEs had previously been assessed as unrelated or of doubtful relationship to risperidone treatment [13] and thus may not have been documented as risperidone AEs in the EHR.

Extrapyramidal symptoms and daytime hypersomnia are common AEs with risperidone therapy and potentially related to risperidone dose. In our cohort, the majority of children with daytime hypersomnia experienced this effect while on a low starting dose of risperidone. An earlier study evaluating the efficacy and safety of low-dose (0.125 mg/day for children weighing 20 to < 45 kg; 0.175 mg/day for children weighing > 45 kg) and high-dose (1.25 mg/day for children weighing 20 to < 45 kg; 1.75 mg/day for children weighing > 45 kg) risperidone or placebo in 96 children and adolescents (aged 5–17 years) with autism reported hypersomnia (somnolence and sedation) following low- and high-dose exposures; however, the AE was more frequent in high-dose than low-dose groups [30]. Similarly, the majority of children in our cohort with extrapyramidal symptoms were on low starting doses of risperidone. Data from multiple fixed-dose (1–16 mg/day and placebo) trials of risperidone in adults with schizophrenia suggested extrapyramidal symptoms are risperidone dose related [31, 32]. Those on placebo or low-dose risperidone (1 mg/day) experienced more extrapyramidal symptoms than those on high doses (2–16 mg/day). Another study had shown that dystonia might occur in susceptible individuals during the first few days of risperidone use, even at low doses [32, 33].

One patient each experienced rare AEs, including droopy eyes, hyperthermia, early menstrual flow, fainting spell, precocious puberty, heavy tongue, hot flashes, multiple bruises, musculoskeletal pain, nervousness, oculogyric crisis, premature adrenarche, and restlessness. While there are reports of risperidone-induced AEs involving the ocular muscles (blepharospasm and oculogyric crisis) [26, 34], and potentially thermoregulatory disorder (febrile seizure) [29], the other rare AEs are not previously reported, and the mechanism is unknown. Some of these rare AEs may be attributed to comorbid conditions or concomitant medications and may not be truly risperidone-related. Nonetheless, it is important to make note of these rare AEs in the future monitoring of risperidone in children and adolescents.

Poor response was the major reason for increasing the dose of risperidone in our patients; of the 94 patients with dose increase to > 1 mg/day, 42.4% had AEs (Table 2 and ESM table). However, this is not surprising as previous studies had shown that higher doses of risperidone are associated with high rates of extrapyramidal symptoms and hypersomnia in children with various behavioral problems [35]. Further, the starting dose of risperidone was decreased in four patients and discontinued in 37 patients due to AEs (Table 2 and ESM table). Four other atypical antipsychotic agents (aripiprazole, olanzapine, paliperidone, and quetiapine) currently have FDA-approved indications for use in children and adolescents [36]. These other agents were used as alternatives to risperidone in our patients after discontinuation due to AEs. Aripiprazole was the most frequently used substitute for risperidone, and this may be attributed to its relatively lower AEs and good tolerability compared with other newer atypical antipsychotic agents [37]. Aripiprazole has been successfully used to address risperidone-induced mild hypothermia in an 11-year-old with schizophrenia [38].

Although the univariate analyses showed that dosing frequency and dose-modification pattern of risperidone were significantly associated with AEs (Table 2), these two factors did not remain significant in the multivariate analysis (Table 3). There is a lack of studies identifying risk factors for risperidone-induced AEs. However, younger age and higher medication dose have been reported as predictors of adverse weight gain in children exposed to risperidone for 8 weeks [39]. Despite weight gain being the most reported AE among our cohort, age at commencement of risperidone and increased dose did not significantly impact the risk for AEs in our cohort. By contrast, use of risperidone to treat self-injurious behavior was associated with a higher risk of AEs compared with children without this behavioral problem. This is a new finding that will be strengthened by validation in an independent dataset. It is noteworthy that children with autism spectrum disorder (ASD) and various forms of chromosomal abnormalities, which constitutes a significant proportion of our patients, are known to have a high prevalence of self-injurious behaviors [40], which might have influenced our observation that self-injurious behaviors are associated with AE risk. It is possible that AEs are reported with higher frequency in this subset, due to more frequent follow-up, higher vigilance for AEs, or more difficulty in discerning drug effects. These individuals may also be receiving additional drugs, contributing to AEs and drug–drug interactions. In addition, risperidone is primarily metabolized by the polymorphic cytochrome P450 2D6 enzyme (CYP2D6) [41]. A study comparing the distribution of CYP2D6*4 and CYP2D6*41 alleles (implicated in the efficacy and adverse effects of risperidone) in patients with ASD and healthy control groups showed higher frequencies of both alleles in patients with ASD [42]. This is a potential confounder that might have contributed to the high odds ratio of AEs among individuals with self-injurious behavior. Our ongoing study of the roles of CYP2D6 polymorphisms in risperidone AEs in children will test this hypothesis. Further, concomitant use of antibiotics was associated with a lower risk of AEs compared with children who did not use antibiotics. One potential mechanism for this observation is increased metabolism of risperidone due to enzymatic induction. An in vitro study demonstrated risperidone metabolism by CYP3A4 and CYP3A5 enzymes [43], which can be induced by antibiotics. Although we did not ascertain whether the antibiotics enhanced the metabolism of risperidone to produce this protective effect and cannot determine causation in this retrospective study, the impact of this minor metabolic pathway and this potential drug–drug interaction merit further investigation.

We acknowledge several limitations. This was a single-center study, and these findings may not be generalizable to the entire pediatric population. However, we believe our findings are robust based on the larger sample size analyzed compared with previous smaller studies [12, 13, 26‐29]. Weight gain and sedation are common adverse effects of some concomitant drugs, such as valproic acid, used by our patients, which could potentially increase the prevalence of risperidone-induced weight gain and hypersomnia reported in this study [44]. Another limitation is that risperidone exposure and the associated AEs were audited retrospectively in the EHR, which may have missing and inaccurate data [45, 46]. For example, an AE ascertained at another hospital may not be captured [47, 48], we may not have complete ascertainment of mild AEs [49], the primary diagnoses and indications for risperidone exposure may not be complete, there may be errors in the documented dosing regimen, and weight and height were not serially assessed at every visit for every individual. Further, patients with early AEs may have been excluded from the study due to the inclusion criteria of ≥ 4 weeks of risperidone therapy. We did not perform causality assessment between the AEs and risperidone to exclude concomitant medications as the likely cause. Generally, AE refers to any problem occurring at the time a medicine is used, whether or not it is identified as a cause of the problem [50]. For this cohort with a high incidence of polypharmacy, other medications or a drug–drug interaction may have been truly responsible for some AEs. Our cohort size was not large enough to explore all possible risk factors (or combinations of risk factors) contributing to risperidone-related AEs. Meta-analysis across many cohorts may enable more granular detail and more precisely guide future prescribing advice.

Risperidone was associated with a significant proportion of one or more AEs among children and adolescents after using the medicine for ≥ 4 weeks. The age at commencement of risperidone, presence of comorbidities, dosing regimen of risperidone, and concomitant use of analgesics or orexigenic medicines did not predict AEs in this study, but there was an increased risk for AEs among patients with self-injurious behavior. Clinicians should be cautious in prescribing risperidone to patients with self-injurious behavior. Further research is needed to identify clinical factors or biomarkers to accurately predict risperidone AEs.