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Do Antipsychotics Have Neurotoxic Effects in Youth?

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Do antipsychotics have neurotoxic effects in youth? In this episode, we’ll be banging the drum of caution about antipsychotic use in children and adolescents. 

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Published On: 03/03/2022

Duration: 11 minutes, 21 seconds

Related Article:Exploring the Potential Neurotoxicity of Antipsychotics in Younger Populations,” The Carlat Child Psychiatry Report, November/December 2019

The American Academy of Child and Adolescent Psychiatry Practice Guidelines for Antipsychotics

Joshua Feder, MD, and Mara Goverman, LCSW, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

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Dr. Feder: Hello! I’m Dr. Joshua Feder, the Editor-in-Chief of The Carlat Child Psychiatry Report.

Mara: And I’m Mara Goverman, a Licensed Clinical Social Worker in Southern California with a private practice.  

Dr. Feder: And in this episode of the The Carlat Psychiatry Podcast, Mara and I will be banging the drum of caution about antipsychotic use in children and adolescents. 

Mara: We will cover the labeled use of antipsychotics in youth, and the big red flags associated with off-label use, including its lack of efficacy as well as the latest research on the negative impact that antipsychotics have on a developing brain. 

Dr. Feder: Before we jump into the major concerns surrounding antipsychotic use in youth, we’re going to discuss the cases in which the use of these drugs are beneficial and well substantiated by quality evidence. 

Mara: First and foremost, it is important to treat psychosis. A recent review by Goff and colleagues shows better long-term treatment outcomes when antipsychotic intervention is initiated earlier in the course of schizophrenia. 

Dr. Feder: What is clearer is the efficacy of using antipsychotics to treat severe irritability in autism spectrum disorder, a central function for child psychiatrists. Studies with large numbers demonstrate excellent responses for aripiprazole and risperidone in this setting. 

Mara: It would be incredibly difficult to effectively manage both schizophrenia and autism without antipsychotics. The extensive research data and strong evidence of efficacy clearly supports the use of antipsychotics in these youth subpopulations. However, we start to run into some serious problems when we start using antipsychotics off-label in youth.

Dr. Feder: Definitely! While the importance of labeled use of antipsychotics is abundantly clear, a 2016 review of medical records estimated that about 65% of antipsychotic prescriptions for children ages 4–18 were for off-label use. Most off-label antipsychotic medication prescriptions are intended to treat ADHD and behavioral or emotional disturbances not otherwise classified. However, evidence for their efficacy in these circumstances is sparse. 

Mara: 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.

Dr. Feder: Most often, off-label antipsychotics are used to treat aggressive behaviors in children and teens. The use of antipsychotics in this subpopulation 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.

Mara: Okay, so there’s definitely some concerns with the efficacy of off-label antipsychotic use in children and teens, but what are the detrimental impacts that these medications have on developing brains?

Dr. Feder: 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. They highlighted findings in animal models that showed an approximate loss of 8%–11% in brain volume compared to controls.

Mara: 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. While most of this research is correlational, not causal, it raises clear concerns. 

Dr. Feder: 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. 

Mara: Jeez, that’s shocking! Doesn’t that create a difficult situation for treating the most severe cases of schizophrenia and irritability in autism? I mean, if a case is so severe, wouldn’t that constitute using a higher dose of an antipsychotic to achieve a higher level of efficacy?

Dr. Feder: Well, not exactly. 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. There is also new evidence that high-dose antipsychotics are linked to a nearly 80% increased risk of death in children and adolescents.

Mara: 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.

Dr. Feder: 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. 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%.

Mara: 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.

So, Dr. Feder, what can clinicians do to reduce the amount of off-label antipsychotic use? 

Dr. Feder: 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.

Mara: Overall,  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. 

Dr. Feder: You can access their working document by clicking the link in the description.

The clinical update is available for subscribers to read in The Carlat Child Psychiatry Report. Subscribers get print issues in the mail and email notifications when new issues are available on the website. Subscriptions also come with full access to all the articles on the website and CME credits. 

Mara: And everything from Carlat Publishing is independently researched and produced. There’s no funding from the pharmaceutical industry. 

Dr. Feder: Yes, the newsletters and books we produce depend entirely on reader support. There are no ads, and our authors don’t receive industry funding. That helps us to bring you unbiased information you can trust. 

Mara: Go to to sign up. You can get a full subscription to any of our four newsletters for $30 off by using the coupon code LISTENER.

As always, thanks for listening and have a great day!


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