At Carlat, we bang the drum of caution about antipsychotic use in children and adolescents. In this article, we pair rising concerns about antipsychotic neurotoxicity with the lack of efficacy evidence for off-label usage.

Labeled use
It is important to treat psychosis. A recent review by Goff and colleagues shows better outcomes for people who receive medication sooner (Goff DC, Am J Psychiatry 2017;174(9):840–849). What is clearer is the efficacy of using antipsychotics to treat severe irritability in autism spectrum disorder (ASD), a central function for child psychiatrists. Studies with large numbers demonstrate excellent responses for aripiprazole and risperidone in this setting (Fallah M, J Child Adolesc Psychopharmacol 2019;29(3):168–180). It is difficult to imagine effective management of both schizophrenia and severe autism without antipsychotics.

Efficacy vs risk in off-label use
The importance of labeled use of antipsychotics is clear, yet a recent review of medical records estimated that 65% of antipsychotic prescriptions for children ages 4–18 were for off-label use (Sohn M et al, Medicine (Baltimore) 2016;95(23):e3784). Most off-label antipsychotic medication prescriptions are intended to treat ADHD and behavioral or emotional disturbances not otherwise classified. Evidence for their efficacy in these circumstances is sparse, however. Recent studies show a lack of efficacy for antipsychotics when treating ADHD. A 2017 systematic review and ­meta-analysis concluded that the best evidence for ADHD treatment is behavioral therapy, stimulants, or a combination of the two (Catalá-López F et al, PLoS One 2017;12(7):e0180355).

Treating aggression in children and teens, the most common target when prescribing off-label antipsychotics, is complex at best. Looking specifically at reducing aggression in children with conduct disorder or oppositional defiant disorder with or without ADHD, another meta-analysis found some positive effects for risperidone, but not for haloperidol or quetiapine (Pringsheim T et al, Can J Psychiatry 2015;60(2):52–61).

High vs low dosage
In residential settings, children requiring frequent seclusion and restraint are often prescribed high doses of antipsychotic medications. However, in a year-long study, higher dosage and frequency of antipsychotic prescriptions didn’t reduce the need for seclusion and restraint in the most ill children (Miller L et al, J Behav Health Serv Res 2013;40(1):97–110). There is also new evidence that high-dose antipsychotics are linked to a nearly 80% increased risk of death in children and adolescents (Ray WA et al, JAMA Psychiatry 2019;76(2):162–171). (Editor’s note: For a more detailed discussion on high-dose antipsychotic use, see CCPR, March/April 2019.)

It is also important to remember that children and adolescents are more sensitive than adults to side effects of weight gain, extrapyramidal symptoms, somnolence, high cholesterol, high prolactin, and type 2 diabetes. Taken together, there is little existing research to support the use of off-label prescriptions of antipsychotic medications for children.

Neurotoxicity
In addition to off-label efficacy concerns, we now have more information on the possible direct neurotoxicity of antipsychotic medications. In a letter to the editor of the Australia & New Zealand Journal of Psychiatry, the authors sound an alarm about the potential for antipsychotic medications to cause brain atrophy (Bastiampillai T et al, Aust N Z J Psychiatry 2019;53(6):499–500). They highlighted findings in animal models that showed an approximate loss of 8%–11% in brain volume compared to controls (Vernon AC et al, Biol Psychiatry 2011;69(10):936–944). In humans, first-episode schizophrenia is associated with brain volume changes in adolescents and young adults, moderated by illness duration, disease severity, substance abuse (particularly alcohol and cannabis), and antipsychotic treatment. In particular, some studies show that higher doses of antipsychotics played a larger part in reductions of brain volumes (Ho BC et al, Arch Gen Psychiatry 2011;68(2):128–137).

Another study of young adults with first-episode psychosis showed more cortical thinning in those on antipsychotic medications compared to both an unmedicated group and a control group. Even so, the medicated group performed better on performance testing and showed more functional activity in the dorsolateral prefrontal cortex than the unmedicated group, despite more thinning in that area (Lesh TA et al, JAMA Psychiatry 2015;72(3):226–234). While most of this research is correlational, not causal, it raises clear concerns.

Minimizing use of antipsychotics
Antipsychotics are often used when comprehensive care is not available. However, studies of comprehensive care show reductions in the perceived need for and use of these medications. A Washington state consultation program flags antipsychotic dosage, patient age, and the combination of medications prescribed (Barclay RP et al, Health Serv Res 2017;52(2):561–578). Prescribers then speak by phone with a child-adolescent psychiatric consultant and discuss alternative interventions. In the 18 months following implementation, high-dose antipsychotic prescriptions for children and adolescents dropped by more than 50%. Programs such as one described by Dr. Ed Levin report similar reductions in antipsychotic use in a residential treatment setting for children receiving treatment for developmental trauma, with emphasis on methods for understanding the reasons for behavioral problems and techniques for de-escalation (Levin EC, J Am Acad Psychoanal Dyn Psychiatry 2009;37(3):519–538).

When prescribing an antipsychotic medication, clarify diagnoses and the range of possible interventions. For instance, when treating ADHD, have the specific medications for ADHD been optimized, has the patient had the benefit of good-quality behavioral therapy, or could school accommodations better meet the patient’s needs? When increasing the dose of an antipsychotic, remember that higher doses usually mean more adverse effects but not always increased efficacy. Good practices are to hold ongoing discussions with the patient and family about the risks and benefits of antipsychotic medications; follow the “start low and go slow” mantra; clarify target dosing for the disorder; monitor for side effects at each visit, including body mass index (BMI); think about the clinical need for each medication; and remember that there is little evidence for simultaneous use of multiple antipsychotic medications in children.

CCPR Verdict: The added concern of direct neurotoxicity of antipsychotic medications makes it imperative for child psychiatrists to improve diagnostic clarity, support comprehensive and rational treatment planning, and reduce dosages and use of antipsychotic medications where possible. Clinical consultation with colleagues is key in generating ideas to achieve such goals. The American Academy of Child and Adolescent Psychiatry is currently developing new practice guidelines for antipsychotic medications, and the working document can be accessed here: www.tinyurl.com/y49kc9zt