Atypical Antipsychotic-Induced Weight Gain in Children and Adolescents: Sometimes Less Is More.

In this issueof JAMAPsychiatry,Anagnostouet al1 present results of a double-blind, placebo-controlled study of metformin forweightmanagement in children and adolescentswith autism spectrum disorder (ASD) treated with an atypical antipsychoticmedication.Metforminwassignificantlymore efficacious than the placebo for decreasingweight gain associatedwith the use of atypical antipsychotics in this population. The primary disadvantage for the active treatment groupwas a significantly higher percentageof treatmentdayswith associatedgastrointestinal adverse events during the 16weeks of the trial. Therewasnodifference in change inmetabolic parametersmeasured inblood, including total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, glucose, fasting insulin, or hemoglobinA1C, between themetformin and placebo groups. Symptomsof irritability (eg, aggression, self-injurious behavior, and severe tantrums) in youths with ASD are common and serious. Aggression can be directed toward parents, siblings, teachers, peers, or strangers. The aggression is typically impulsive and at times unpredictable. Asking an individual to do something he or she does not want to do, interrupting a preferred repetitive/ritualistic activity, or abruptly changing theplanned schedule for theday canprecipitate aggression.Self-injuriousbehavior can range inseverity frombiting fingernails when anxious to bringing one’s knee to one’s head repeatedly, resulting in subdural hematoma or detached retina. When young children with ASD have a temper tantrum inpublic, the parentmaybe able to pick themupand whisk themaway from the setting. As the child ages, thismay no longerbepossible; emergencymedicalpersonnelmayneed to be called, often leaving the parent feeling helpless and inadequate. At times, chronic irritability can lead to the child’s removal from school or from the family home and result in placement in a residential setting. Irritability canbedevastating for the individual, their family, and their support network. Treatment intervention is usually necessary. Risperidone and aripiprazole are atypical antipsychotics approved by the US Food and Drug Administration for treatmentof irritability in childrenandadolescentswithASD.They are generally regarded as first-line treatment. Each medication has been shown in larger-scale randomized clinical trials tobe significantlymoreeffective than theplacebo for this purpose. Risperidone and aripiprazole have serious adverse effects. Some they share in common include increased appetite, weight gain, sedation (often transient), and the risk of extrapyramidal symptoms including tardive dyskinesia. Increased appetite and weight gain are associated with each of the atypical antipsychotics except ziprasidone. Atypical antipsychotic-induced weight gain is more prevalent in children than adults. Youths with ASD and significant irritability may need to be treated with an atypical antipsychotic for many years; adequate studies evaluating the long-termeffect of this class of drugs on weight gain and related medical comorbidity, including metabolic dysregulation, are lacking. Beyond the negative medical factors associated with the use of atypical antipsychotics in children with ASD, additional behavioral and psychosocial challenges may arise. It is notunusual for apreferred food tobeusedas a rewardbycaregiverswhen attempting to altermaladaptive behavior in their children. If the child develops a significant increase in appetite and associated weight gain with an atypical antipsychotic, itmaybecomenecessary for the caregiver towithhold the preferred food. This can result in an escalation of irritability and compound the problem. As children with ASD gain weightandbecomeoverweightorobese, their self-esteemmay decrease. Theymay find themselves at an even greater risk of bullying fromothers.Moreover, tobe concrete, as a childgains weight, they get bigger. The hole that results from hitting the wall in their bedroombecomes larger simply owing to the extra weight behind the force of their strike. Clearly,Anagnostouetal1understandthedilemmaour field faces inbalancing the risk-benefit ratio of treatingyouthswith ASD with atypical antipsychotics. They have identified a potentialmedicationcotreatment tohelpmitigate theweightgain associatedwithatypicalantipsychoticuse inchildrenwithASD. They also realize the limitations of their study. They state that their sample size is small. They question whether the length of the metformin treatment may have been too short to capture potential benefits in metabolic measures. They wonder whether coadministration ofmetformin at the onset of atypical antipsychotic use prevents initial weight gain. Larger and longer-term studies of metformin administration in youths with ASD treated with an atypical antipsychotic will be important to address these concerns and remaining questions. Considering themagnitude and prevalence of significant weight gain and associatedmedical sequelae associatedwith atypical antipsychotic use in children with ASD, it is important to consider additional strategies to address this persisRelated article page 928 Opinion