Ryan S. Sultan, MD

The Complexity of Off-Label Antipsychotic Prescribing for Severe Behavior in Children

Article Type: Viewpoint / Commentary
Date: September 2024
Status: Peer-Reviewed Publication Format

Abstract

This viewpoint article examines the complex landscape of off-label antipsychotic prescribing for children with severe behavioral disturbances. It distinguishes between supported and unsupported off-label prescribing practices, reviews the evidence base for antipsychotic use in pediatric populations with disruptive behavior disorders, and argues that psychiatric specialists are best equipped to make these complex clinical decisions.

Introduction

Antipsychotic medications have become increasingly common treatment options for the management of several child and adolescent psychiatric problems.^1,2 Prescribing of antipsychotics to children has generated public and professional concern over the appropriate role of antipsychotics in the management of severe behavioral disturbance in Disruptive Behavior Disorders (DBDs). Criticism exists in mainstream media, with discussions of restricting off-label prescribing and proposed quality safety measures such as the Nation Committee for Quality Assurance's Healthcare Effectiveness Data and Information Set (HEDIS). Antipsychotic prescribing to children without FDA indication is a core criticism. This story of off-label antipsychotic prescribing is complex as there is evidence for efficacy and countervailing evidence for safety concerns.

FDA Indications and Evidence-Based Medicine

Critiques of antipsychotic prescribing for aggression in children cite the lack of an FDA indication as proof that the use is not grounded in scientific evidence or an appropriate standard of care. However, FDA indications do not encompass the full breath of knowledge that we utilize as psychiatrists to treat our patients. The studies that generate FDA indications represent part of the available research. Clinical decision-making for treatment of children with antipsychotic medications integrates safety data, FDA data, scholarly peer-reviewed literature, clinical presentation and a risk-benefit analysis.

Safety Concerns

Substantial research has demonstrated evidence for safety concerns regarding the prescribing of antipsychotics. Atypical antipsychotics have evidence for metabolic effects, most notably, weight gain.⁷ Prescribing may be occurring prematurely, without first consideration of psychosocial treatment.⁸ There is lack of long-term safety data regarding these medications effects on the central nervous system development. While these concerns are valid, they are only part of the story of antipsychotic prescribing for children with aggression.

Understanding FDA Approval

FDA data and indications are one resource clinician's use in evaluating antipsychotic for children but it is not complete. The FDA approval process reviews specific, industry-funded trials for medications attempting to come to market. The FDA examines several phases of trials designed to answer questions of safety, tolerability and efficacy. Medications that receive an FDA approval for treatment of a disorder have been determined to be safe, tolerable and effective for that disorder. Due to limited financial incentives, the pharmaceutical industry will not petition for other potential indications for a medication. Therefore, when a medication is prescribed off-label or without a FDA indication, it does not necessarily imply the medication is not safe, tolerable, or effective.

The FDA is comfortable with off-label prescribing as the FDA does not envision their role as regulating the practice of medicine. The FDA makes clear that 'neither the FDA nor the Federal government regulate the practice of medicine. Any approved product may be used by a licensed practitioner for uses other than those stated in the product label [off label prescribing]'.²⁰ In cases regarding the establishing the standard of care, the FDA approval package inserts have little played little role in the establishing of the standard of care. Legal scholars have described the primary purpose of FDA labels is to guide appropriate industry marketing.²¹ Understanding the FDA's important, yet limited, role in the evaluation of antipsychotic prescribing in children allows us to appreciate the concept of supported off-label prescribing.

Supported vs. Unsupported Off-Label Prescribing

Off-label prescribing is a common and important source of treatment throughout medicine, particularly psychiatry. Many of the medications that are prescribed off-label have evidence-based and clinical literature to support their use. This distinction between supported and unsupported off-label prescribing practices is important. Supported off-label prescribing is the use of medications for a non-FDA approved indication when there is moderate to high certainty of a net benefit. That certainly is informed by known scientific evidence which grounds the practice. Unsupported off-label prescribing is use that is suppositional or even investigative. In unsupported prescribing, there is a low or very low level of certainly that the medicine will have a net benefit.

Evidence for Antipsychotics in DBD

Some antipsychotics are examples of supportive off-label prescribing in pediatric populations. For example, Risperdal demonstrates effectiveness in several double-blind placebo-control trials for the use of severe behavioral disturbances in children with DBD. A 6-month trial of Risperdal, reduced reoccurrence of symptoms of disruptive behavioral disorders to 37 days from 119 day compared with placebo.¹⁵ In a 10-week trial, Risperdal ameliorated symptoms of aggression in conduct disorder.¹⁶ In children with severe aggression and Attention-Deficit/Hyperactive Disorder, optimized on a stimulant and already undergoing parent training Risperdal demonstrated reduction of aggression.¹⁷ While these studies demonstrate efficacy and are similar to those used to receive a FDA-indications, the FDA does not recognize non-petitioned, non-industry funded trials for their approval process.

Historical FDA Data and Neurobiology

There is historical FDA data and neurobiology to support the use of antipsychotics for severe behavioral problems such as aggression. While atypical antipsychotics lack a FDA indication, several typical antipsychotics have FDA indications for children with disruptive behavior. Haloperidol is FDA approved for three years and older for agitation. Chlorpromazine is approved for 6 months or greater for severe behavioral problems. This effect is supported by the neuroscience of aggression, dopamine, serotonin and the mechanisms of actions of antipsychotic mediations. This information on typical antipsychotics for severe behavior disturbances, combined with the known RCTs for atypicals is important as it suggests class effect of efficacy.

Clinical Prescribing Patterns

Large survey and prescription data supports that clinician's primary target for off-label prescribing in children are severe behavior disturbances. Retail prescribing data analyses demonstrate primary uses including aggression and impulsivity in DBD.¹⁰ Medicaid claims of antipsychotic prescribing show similar trends in use for aggression, severe mood instability, and impulsivity.¹² A recent survey of 340 psychiatrists, identified by the American Medical Association found that most providers agreed that antipsychotics were appropriate for off-label use only in situations of severe aggression, such as being explosive, destroying property or intentionally harming self.⁹ Inpatient psychiatrists report being more likely to utilize antipsychotics for children in their practice due the greater severity of illness treated compared with their outpatient colleagues.¹³ These data demonstrate that clinicians are prescribing antipsychotics for supported off-label indications.

Unsupported Off-Label Use

While much of the prescribing of antipsychotics to pediatric populations with severe behavioral disturbances is supported off-label use, there is also evidence of unsupported off-label prescribing antipsychotic in pediatric populations. Prescription and Medicaid administrative data establish antipsychotics being used for nonspecific mood or anxiety and sleeping issues.^10,12 Incomplete or poor coding by providers may account for some of this prescribing, but not likely all of it. Primary use of antipsychotics for sleep or anxiety is potentially concerning for these disorders. It represents unsupported off-label prescribing of antipsychotics for children. More importantly though, there are alternative treatments available which are more specific and better tolerated than antipsychotics.

Clinical Decision-Making

Treatment of severe behavioral disturbances with antipsychotics is an example of evidence-based off-label prescribing. The decision to prescribe an antipsychotic to a child is a complicated one. Antipsychotics have potentially adverse metabolic effects for children. FDA indications for antipsychotics are incomplete, as they do not capture the full breath of evidence-based literature available. Knowledge and comfort with supported off-label prescribing of antipsychotics requires a deep knowledge of the literature. Further, children with aggression are presenting with severe, acute and urgent symptoms. Thorough and complete understanding of a child's presentation, diagnoses and family system is required for appropriate intervention. This comprehensive evaluation will guide the use of appropriate interventions and treatment, both pharmacologic and non-pharmacologic. Most importantly, it will reduce unsupportive off-label prescribing practices. Significant understanding is required to effectively address all the components of antipsychotic prescribing to children.

Role of Psychiatrists

This multifaceted situation of antipsychotic use in pediatric populations dictates that psychiatrists are the best equipped to integrate the risk and benefits of antipsychotics, the complex presentations of these children and the evidence-based literature on the use of antipsychotics in children. It is unrealistic of psychiatry to expect other specialties to adequately complete the same task. In fact, given that Medicaid survey data shows non-psychiatrists were less likely to follow best practice guidelines regarding indications for antipsychotics in children, expecting other specialties to address this may foster more unsupported off-label prescribing of antipsychotics to children.¹²

Recommendations

Given the concerns about appropriateness and safety, the decision for prescribing antipsychotic should be made by a psychiatrist. This will maximize the likelihood that antipsychotics are used judiciously and for supported off-label indications in children. To achieve this goal of psychiatrist evaluations, we should be working to bring children to specialists quickly through investing in rapid access systems such as telehealth, integrated care models as well as addressing the shortage of child psychiatrists. These interventions will help to decrease any inappropriate and unsupported prescribing of antipsychotics as it moves the decision making of these medications in the hands of individuals who specialize in them.

References

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3. Olfson M, Blanco C, Liu L, Moreno C, Laje G. National trends in the outpatient treatment of children and adolescents with antipsychotic drugs. Arch Gen Psychiatry. 2006;63(6):679-685.
4. Pathak P, West D, Martin BC, et al. Evidence-based use of second-generation antipsychotics in a state Medicaid pediatric population, 2001-2005. Psychiatr Serv. 2010;61(2):123-129.
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15. Reyes M, Buitelaar J, Toren P, Augustyns I, Eerdekens M. A randomized, double-blind, placebo-controlled study of risperidone maintenance treatment in children and adolescents with disruptive behavior disorders. Am J Psychiatry. 2006;163(3):402-410.
16. Findling RL, McNamara NK, Branicky LA, et al. A double-blind pilot study of risperidone in the treatment of conduct disorder. J Am Acad Child Adolesc Psychiatry. 2000;39(4):509-516.
17. Aman MG, Bukstein OG, Gadow KD, et al. What does risperidone add to parent training and stimulant for severe aggression in child attention-deficit/hyperactivity disorder? J Am Acad Child Adolesc Psychiatry. 2014;53(1):47-60.e1.
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19. Center for Drug Evaluation and Research (CDER). US Food and Drug Administration. Oncology Tools: A Short Tour. 2003.
20. Chen DT, Wynia MK, Moloney RM, Alexander GC. U.S. physician knowledge of the FDA-approved indications and evidence base for commonly prescribed drugs: results of a national survey. Pharmacoepidemiol Drug Saf. 2009;18(11):1094-1100.

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• Current Research - Ongoing studies
• Research Grants - NIH-funded studies
• Professional Profile - Academic background and expertise