Antipsychotic Medications for Low-Income Preschoolers: Long Duration and Psychotropic Medication Polypharmacy

The current longitudinal study detailed antipsychotic medication use and duration in a cohort of preschoolers in a southeastern state from 2012 to 2017 who were receiving Medicaid and were prescribed an antipsychotic in 2012. These children were treated with antipsychotics for long durations, with significant rates of concurrent medication use. The mean duration of exposure to antipsychotic medications in our cohort was 2.6±1.7 years, but 86 children (27%) had at least 4 years exposure. This group was notable for having increased comorbid conditions and being treated with polypharmacy.

Little evidence related to the efficacy or safety of using antipsychotics for preschool children is available. Few antipsychotics have been approved by the U.S. Food and Drug Administration (FDA) for use in this population. The only FDA-approved second-generation antipsychotic for children <6 years old is risperidone for the treatment of irritability associated with ASD (12), and aripiprazole has similar indications starting at age 6.

Psychostimulants and alpha-agonists were the most common additional categories of medications used, suggesting that providers are diagnosing and managing ADHD and disruptive behavior among young children. Also, the diagnosis of DMDD was significantly associated with duration of antipsychotic use. This diagnosis, added to DSM-5 in 2013, includes criteria of temper outbursts out of proportion to the situation and inconsistent with developmental level (13). This diagnosis should not be used before the age of 6 years, so the number of preschool children in our sample treated with antipsychotic medications for DMDD and the lack of evidence-based treatment guidelines for this diagnosis raise concerns about care quality (14). Recent studies, such as the Treatment of Severe Childhood Aggression study (15), suggest that adding risperidone, after initial implementation of psychostimulants and parent-management training, to treat complex ADHD can be beneficial. But the efficacy and safety for children <6 years are unknown. Insomnia is also a frequent target of treatment, given the number of children receiving clonidine and trazodone.

Polypharmacy was a significant concern for our cohort. About one-third of our population received polypharmacy, with four or more classes of medications at some point in our study, including 55% (N=47) of the children with the most exposure to antipsychotic medications. Safety risks of polypharmacy include increased adverse events, drug interactions, and weight gain (16). Furthermore, the addition of antipsychotics to medication combinations may lower the seizure threshold, which could be a particular concern for children with known seizures, autism, and neurodevelopmental concerns (17, 18). There is very little evidence to guide the efficacy and safety of polypharmacy among preschool-age children, so research and problem solving are clearly needed (19).

The diagnoses identified in our cohort suggest that the children in our sample had complex mental health problems, including developmental, emotional, and behavioral difficulties, and 20% (N=63) were in foster care. Despite receiving multiple forms of treatment, the children in our cohort struggled with high rates of inpatient and ED utilization: 277 children (88%) had an ED visit, and 107 (34%) had an inpatient hospitalization over the study period. Our study did not separately consider the reasons for these visits, but other researchers have documented increases in inpatient hospitalizations and ED visits for mental health reasons among this population (20).

Our data suggest that professional guidelines for monitoring young children receiving antipsychotics are not being consistently followed. Some children (N=50, 16%) did not have antipsychotics prescribed by a psychiatrist, and 6% (N=19) had no medical claims from a PCP over the study period. In our cohort, 25% (N=80) of the children did not undergo a glucose test, and over half (N=166, 53%) did not have a lipid test. Preschool children can experience known adverse effects of antipsychotics, including rapid weight gain and metabolic dysfunction (21–25). The National Committee for Quality Assurance has recommended metabolic monitoring and use of first-line psychosocial care as measures for safe and judicious antipsychotic medication use among youths, but implementation varies by health care plan (26), and a minority of young children on Medicaid may receive psychosocial treatments before receiving antipsychotic treatment (27). Providers may be less likely to monitor children on antipsychotics for metabolic adverse effects (28). Younger children are less likely than teenagers to have baseline glucose screening (29) even though younger children may be more likely than older individuals to have a significant increase in glucose within the first 6 months of treatment (30).

Concerns have been raised about the duration of antipsychotic use among youths receiving Medicaid (31) as a contributing factor to the development of long-term adverse effects, such as type 2 diabetes (9, 32). In a cohort study, <3% of children ages 5–15 years were diagnosed as having insulin resistance (33), but children <10 years comprise a small but increasing number of children diagnosed as having type 2 diabetes mellitus (34), which has been reported among children as young as 4 years (35). Because only 42% (N=131) of our cohort received recommended metabolic monitoring over the years of the study, rates of metabolic abnormalities could be higher. We found that 9% (N=28) of our cohort had metabolic dysfunction, but it is difficult to compare this finding with those of other reports describing rates of metabolic abnormalities in preschool populations.

Many safety concerns exist for the use of antipsychotics for preschool-age children. Variations in pharmacokinetics may place children at higher risk for some adverse effects (36). The potential neurobehavioral toxicity to youths treated with these medications, especially preschool-age children, is unknown. As the developing brain matures, multiple synapses and circuits form to create the foundation for the adult brain. Immature brains have a great degree of plasticity, meaning the brain is very sensitive to environmental stimulation. In the case of psychotropic medication, an adult brain may temporarily accommodate the effect of a drug, but the juvenile brain assimilates the drug into its system, producing permanent alterations in the system (37). The administration of psychotropic medications, including antipsychotics, may have lifelong effects on brain function and structure (38).

Because of the complex nature of investigating these questions in humans, much of our understanding on the long-term effects of antipsychotics on the brain and behavior come from animal studies that raise questions about potential alterations in brain structure, executive functioning, emotional regulation, and maternal-offspring interaction (39–43). These findings suggest that chronic antipsychotic use in pediatric populations (e.g., treatment for the symptoms of autism) could modify brain development and alter neural set points for specific behaviors during adulthood. More research is needed to explore these questions.

Additional research is also needed to identify the best strategies for treating young children with complex mental health problems. Our results show that children received antipsychotic prescriptions from multiple prescribers over the course of the study. This pattern highlights a need for communication among all treating clinicians and parents or guardians to understand the rationale and indications behind ongoing antipsychotic use among children and to review alternative treatment options. Systems-of-care treatment approaches that focus on the environment of the child and offer case management services could help (44). In addition to targeting social determinants of health risk factors, such a system could ensure that children and families receive collaborative care based on evidence-based therapies and individualized support to increase rates of metabolic monitoring and guidance for nutrition and exercise management.

Increased psychotropic medication monitoring is an element of improved health care oversight and coordination for children (45). Increased attention to antipsychotic use within the preschool population may identify cases where additional services can be implemented to reduce the use of these medications and improve long-term outcomes. Given these concerns, many states have built a prior authorization process that detects and limits the use of antipsychotics for children <6 years (6, 46). In our state, all Medicaid services were organized into managed care organizations in 2013, and various prior authorization procedures for antipsychotic medications were introduced in later years.

This study utilized administrative claims data, with known limitations (47). We studied only children with continuous enrollment over the study period to examine long-term covariates, so our population may have had additional risk factors compared with children who were not continuously enrolled. Children entered the cohort if they had received an antipsychotic medication at any time in 2012, and we studied descriptive variables for the subsequent years when children received an antipsychotic, potentially reducing the accuracy of our longitudinal findings. Diagnostic data were reported by clinicians and limited to four diagnoses per claim, raising the possibility of errors in billing procedures. In addition, the introduction of DSM-5 in 2013 may have altered the associations between diagnoses and antipsychotic use in our cohort. The accuracy of provider identification was limited, and our provider information did not distinguish child psychiatrists as a separate provider type. We did not separate out inpatient and ED claims data by nature of the visit nor did we examine other eligibility categories. Pharmacy claims were generated only if a prescription was filled, so actual prescribing practices by providers could not be determined. Administrative data did not allow us to determine the appropriateness of the diagnosis or treatments. Our study represents Medicaid claims from one state, so it is unknown whether our findings are generalizable to other states.

Some preschool-age children receive antipsychotic medications and concurrent treatment with other drug classes for substantial periods. Further study is needed to identify evidence-based practices to improve care quality and outcomes for this vulnerable population.