CCPR: We discourage the use of second-generation antipsychotics (SGAs) unless they are truly needed because of their metabolic and neurologic side effects. What might it feel like physically and psychologically for a teen who has gained a lot of weight?
Dr. Dopheide: It’s difficult for a child to cope with gaining weight. They’re developing their sense of self and they’re naturally comparing themselves to others, and they can’t fit into the right fashions, they can’t do sports, they feel they look bad or they’re not cool. It damages their self-esteem and makes them more subject to bullying. All of these things need to be taken into account. It is very challenging.

CCPR: Are there some kids and teens who are more likely to have metabolic problems with SGAs? 
Dr. Dopheide: Children prescribed antipsychotics for any indication—psychosis, bipolar disorder (BD), autism spectrum disorder, or aggression—are prone to hunger, weight gain, hyperglycemia, dyslipidemia, abdominal obesity, even pulse and blood pressure changes.

CCPR: Is there something about the conditions themselves, or is it the exposure to the medication that’s doing this? 
Dr. Dopheide: The cause of metabolic side effects is multifactorial: genetic predisposition, lifestyle issues (insufficient exercise, poor diet, irregular sleep), antipsychotics, and concomitant medications. Autistic kids often have restrictive, carbohydrate-rich diets that lead to weight gain.

CCPR: Is the weight gain entirely due to hunger? 
Dr. Dopheide: Even youth who don’t complain of hunger may gain weight and develop diabetes and dyslipidemia, so it’s not just that they’re eating more, although that is a big factor.

CCPR: Are there good studies on antipsychotic-associated weight gain in youth?
Dr. Dopheide: There was an analysis of about 16,000 SGA recipients, ages 5 to 19, from an ambulatory care database from 2016 to 2021, taking an SGA for 90 days up to 24 months (Lyu N et al, J Child Adolesc Psychopharmacol 2024;34(4):201–209). About 35%–60% of the youth demonstrated clinically significant weight gain associated with the antipsychotic treatment. 

CCPR: What were the risk factors for metabolic side effects in this study?
Dr. Dopheide: The risk factors for rapid, clinically significant weight gain included male gender, age under 12, non-Hispanic white ethnicity, and lower baseline BMI Z-score. BMI Z-scores account for age-related weight gain in youth who are expected to gain some weight as they grow.

CCPR: Are there specific populations of children and adolescents at risk for metabolic side effects with SGAs? 
Dr. Dopheide: Available evidence suggests that autistic children can experience more weight gain compared to kids with other diagnoses. This could be because they start taking the antipsychotic at a younger age and often for longer periods of time, in addition to potentially having less physical activity overall.

CCPR: How much of antipsychotic weight gain is due to genetic predisposition?
Dr. Dopheide: The predisposition to antipsychotic metabolic effects is strong, about 60%–80% genetic. We know of 13 single-nucleotide polymorphisms (SNPs) and nine genes associated with weight gain from antipsychotics. Antipsychotic-related weight gain is polygenic and associated with specific gene variants, especially genes coding for antipsychotic pharmacodynamic targets, such as 5HT2C receptors. Several studies found that the T allele seems to be protective against antipsychotic-related weight gain, perhaps by enhancing gene expression of 5HT2C, which partially counterbalances the 5HT2C antagonistic antipsychotic effect.

CCPR: Is there genetic testing to assess the risk of metabolic side effects of SGAs in children and teens? 
Dr. Dopheide: Genetic testing for this risk is not useful with so many SNPs involved and different receptors. Predisposition to this kind of weight gain can depend on the receptor density of an individual patient. Practically speaking, if your patient has rapid weight gain in the first two to four weeks, they are prone to the metabolic side effects of SGAs.

CCPR: What do we know about how social determinants of care impact metabolic side effects of SGAs?
Dr. Dopheide: The IVAC database of private-pay ambulatory care showed white non-Hispanic kids were at more risk. Other social determinants impact whether a child has access to a healthy diet. If a family struggles with food insecurity, meals may consist of lower-cost, higher-calorie food with simple carbohydrates rather than lean protein and complex carbohydrates or whole grains, and that can certainly lead to weight gain. Another important social determinant has to do with housing. Youths who are in out-of-home placements, who are autistic or have an intellectual disability, may be prescribed SGAs without good medical care (including lack of monitoring and lack of intervention for metabolic side effects).

CCPR: What do you think of using GLP-1 agonists to prevent or treat weight gain and other metabolic side effects of SGAs?
Dr. Dopheide: I am much more comfortable with dietary/nutritional interventions, metformin, and making sure they get regular exercise and that they sleep well at night. There’s also some evidence that regular melatonin, if it’s helping them sleep, can decrease metabolic side effects (Al Jumaili W et al, Child Psychiatry Hum Dev 2024;55(2):479–487). The GLP-1 agonists are exciting, but I haven’t seen enough safety data in youth, and especially for this indication.

CCPR: Do you ever use topiramate to prevent or treat weight gain and other metabolic side effects of SGAs in kids? 
Dr. Dopheide: Sometimes, but we typically discontinue topiramate when people come to us on it because of cognitive effects, sedation, interference in school performance, or paresthesia.

CCPR: Do you worry about metabolic acidosis with metformin, particularly in combination with other medicines like topiramate?
Dr. Dopheide: I have not seen it. But we need to monitor for that and also periodically check renal function, especially in youth with stimulant use disorders that can impact kidney function because of excessive vasoconstriction from stimulants.

CCPR: Right. How soon are you likely to start metformin? 
Dr. Dopheide: If they’re gaining weight within the first week or two, we try to start it as soon as possible.

CCPR: Would you ever start metformin before you see weight gain?
Dr. Dopheide: I would not start metformin in someone taking olanzapine when they’re not gaining weight. They could be in the 40%–60% who don’t gain excessive weight. I saw a 25-year-old with autism spectrum disorder and food sensitivities who started olanzapine for aggression as a teen and he’s still got a BMI of 16.5 with normal HgA1c and lipid panel.

CCPR: Which SGAs are the bigger offenders for metabolic problems in kids and teens?
Dr. Dopheide: Similar to adults, clozapine or olanzapine are associated with the most metabolic problems in children and adolescents, then quetiapine and risperidone (I include paliperidone with risperidone). Aripiprazole and lurasidone are lower risk, but youth can still develop significant metabolic complications on these. The only weight-neutral antipsychotic is ziprasidone, but a meta-analysis showed that ziprasidone is no better than placebo for schizophrenia in youth (Correll CU et al, Eur Neuropsychopharmacol 2024;82:57–71). You might try it for other indications, particularly if they’re not aggressive. There is some evidence for ziprasidone to help with aggression in autism or intellectual disability, but I don’t have much confidence in it (Fitzpatrick SE et al, Neuropsychiatr Dis Treat 2016;12:1525–1538). 

CCPR: What do you think of lurasidone compared to olanzapine or risperidone for metabolic impact and efficacy in psychosis?
Dr. Dopheide: Lurasidone poses a lower metabolic risk, but it is not as effective as olanzapine and risperidone for positive symptoms of schizophrenia, hallucinations, disorganized thinking, delusions, or paranoia. I wouldn’t recommend olanzapine as the first antipsychotic initiated for psychosis, a mood disorder, or aggression with autism because it’s got the highest metabolic risk.

CCPR: Do you routinely recommend SGAs for irritability or aggression?
Dr. Dopheide: Of course not. We want to do whatever we can with nonpharmacologic means (ie, behavioral plans) and other medications before we use SGAs. However, if nothing is working, we sometimes do need to resort to these medications. For irritability in autism, I would try risperidone or aripiprazole because those tend to have higher-quality evidence supporting effectiveness and safety. If I have a youth who is extremely aggressive because of their psychosis, paranoia, BD, or schizoaffective disorder, then I may go with risperidone first. If I have someone who is less aggressive, I go with aripiprazole first. If the aripiprazole works, it’s likely to be better metabolically. It is also prolactin-sparing and therefore has less potential to lead to softer, more brittle bones and fracture risk. I’m always hopeful that aripiprazole will work, but I have more confidence in risperidone, which does elevate prolactin, increasing risks of fracture and precocious puberty.

CCPR: Would you use that approach across the board diagnostically with affective disorders, autism, and aggression? 
Dr. Dopheide: Not across the board. For aggression in ADHD, Blader found that most of the time if we adjust dosing or switch between methylphenidate or dextroamphetamine it works well, and if not then we might try valproate or risperidone because nothing else has good data (Blader JC et al, J Am Acad Child Adolesc Psychiatry 2021;60(2):236–251). I also consider quetiapine for people with BD who need to sleep, but not if they are psychotic. 

CCPR: What is your approach with SGAs to treat schizophrenia in youth? 
Dr. Dopheide: I advocate for families to consider clozapine in cases of clear, genetically linked schizophrenia (not substance related). Schizophrenia is associated with deterioration of the brain over time. We’re seeing data that when clozapine is used within the first one to two years of the initial presentation of child- or adolescent-onset schizophrenia, it has a better chance to be effective before the deterioration of the brain has started (Griffiths K et al, Psychol Med 2021;51:376–386). Early use of clozapine can preserve brain function. I discuss clozapine, risperidone, and aripiprazole and cover the pros and cons of each, making sure the family knows clozapine is the most effective for schizophrenia in youth. If they don’t want to go with clozapine, I recommend risperidone. If there are more negative symptoms and not much aggression, I’ll recommend aripiprazole. 

CCPR: There’s been talk about relieving some of the monitoring requirements for clozapine. 
Dr. Dopheide: Yes, on February 24, 2025, FDA removed REMS status for clozapine. This removal will likely make it possible for more youth with schizophrenia to receive clozapine trials earlier in the course of illness when clozapine can be more effective at lower doses (Ballon JS et al, J Clin Psychopharmacol 2018;38(3):234–238; Adnan M et al, J Child Adolesc Psychopharmacol 2022;32(1):2–11).

CCPR: How do you talk with patients and parents about these issues? 
Dr. Dopheide: It’s difficult for families to accept that their child has a lifelong condition. Start with empathy and hope and let them know that they’re not alone. I go over the pros and cons of each medication, including sedation and neurological side effects. When I talk about metabolic side effects, I let them know that the most effective treatments often carry more risk of weight gain. I talk to them about the 35%–60% risk of weight gain, that it’s largely genetic, but it’s not anyone’s fault. I talk to them about diet, nutrition, sleep, exercise, and metformin. I also might talk about prebiotics and probiotics and studies on modifying gut flora to reduce metabolic side effects (Samochowiec J and Misiak B, Curr Opin Psychiatry 2021;34(5):503–507). I tell them that if the patient starts gaining a lot of weight, we’ve got to check them regularly for their blood sugar and their fats in the blood to see if they’re developing any metabolic complications. (Editor’s note: Additional approaches such as ketogenic diets and tetrahydrolipstatin [Orlistat] have some early studies in adults for preventing weight gain with SGAs but do not have meaningful research in children and teens.)

CCPR: Are there specific resources you recommend for families of youth with schizophrenia?
Dr. Dopheide: There are many resources, including other families dealing with schizophrenia, in addition to clinicians with information and guidance. Dr. Robert Laitman has started “Team Daniel” for schizophrenia in youth. He advocates for the EASE model for optimizing clozapine in new-onset schizophrenia: early use, assertive monitoring, slow titration, and engagement/support. This leads to a healthier life (Laitman RS et al, Schizophr Res 2023;261:203–205). 

CCPR: Do you have an overall philosophy on using SGAs in children and teens? 
Dr. Dopheide: Start with medications that have more research to support efficacy because when symptoms are under control, there is less risk of adverse outcomes like suicide, traffic accidents, aggression, and assaultiveness. When symptoms are treated effectively, quality of life for the child and the family improves. (Editor’s note: When patients are doing better for 6–12 months, we recommend considering gentle reduction and, if clinically possible, the discontinuation of SGAs to reduce risks of long-term side effects. See CCPR Oct/Nov/Dec 2023.)

CCPR: Thank you for your time, Dr. Dopheide.