As discussed in a previous newsletter, psychotropic medications, particularly antipsychotics, can lead to clinically significant weight gain. Second-generation antipsychotics, such as olanzapine and clozapine, are believed to disrupt glucose, lipid, and appetite regulation by acting on dopamine, serotonin, histamine, and muscarinic receptors. These medications also influence hormones such as leptin, adiponectin, and ghrelin, promoting increased food intake, adiposity, and insulin resistance. Weight gain tends to occur most rapidly in the early stages of treatment and is difficult to reverse.
Antipsychotics are frequently prescribed to children and adolescents for both FDA-approved and off-label indications, including psychosis, bipolar disorder, irritability associated with autism spectrum disorder, and treatment-resistant depression. Youth are particularly vulnerable to antipsychotic-induced weight gain, with an average increase of 5 kg (11 lbs) and a 1.5-point rise in BMI over a 12-month period.
Initial Management Strategies
First-line management involves lifestyle and behavioral interventions. Providers are encouraged to share this handout with patients and families: AACAP Facts for Families #94.
Medication choice also plays a critical role. When clinically appropriate, opt for antipsychotics with lower metabolic risk, and follow a “start low, go slow” dosing approach. If significant weight gain occurs, switching to a more weight-neutral antipsychotic may be considered. It is also important to adhere to metabolic monitoring guidelines:
– Weight/BMI: Baseline, 4 weeks, 8 weeks, 12 weeks, 6 months, then annually
– Fasting glucose/HbA1c, lipid panel, BP: Baseline, 12 weeks, 6 months, then annually
If these measures prove insufficient, pharmacological interventions may be considered.
Pharmacological Options
Metformin. Metformin is the most well-studied and widely accepted first-line pharmacological treatment for antipsychotic-induced weight gain. It reduces glucose absorption, hepatic gluconeogenesis, insulin resistance, cholesterol, and appetite. Existing research supports its efficacy in both adults and youth. One meta-analysis including individuals under 20 found metformin led to nearly 5 lbs of weight loss, reduced BMI z-scores, and improved insulin sensitivity after 12–16 weeks of treatment. It is generally well tolerated and does not worsen psychiatric symptoms. Side effects include nausea, vomiting, and diarrhea; rare but serious adverse effects include lactic acidosis. Metformin may be more effective in first-episode psychosis and for prevention rather than reversal of weight gain. Below are dosing recommendations:
– 6-9 years old: 250 mg with evening meal for one week, then 250 mg twice daily for one week, then 500 mg twice daily
– 10-17 years old: 250 mg with evening meal for one week, then 250 mg twice daily for one week, then 500 mg twice daily for one week, then 850 mg twice daily
GLP-1 Receptor Agonists (GLP-1RAs). GLP-1RAs like liraglutide show promise in adults on antipsychotics for reducing weight, BMI, waist circumference, HbA1c, and LDL cholesterol, without adverse psychiatric effects. Liraglutide and semaglutide are FDA-approved for obesity in adolescents aged 12 and older; however, their use for antipsychotic-induced weight gain in youth remains unstudied. The potential benefits of GLP-1RAs need to be weighed against potential psychiatric side effects, which are not yet fully understood.
Histamine Receptor Agonists. Betahistine, an H1 receptor agonist, has shown efficacy in mitigating olanzapine-induced weight gain in adult studies and in one adolescent study. In one review, betahistine added to olanzapine resulted in a 1.04 kg weight loss over 12 weeks. This effect has not been demonstrated with other antipsychotics. Reported side effects include mild constipation and sleep disturbances.
Other Medications. Topiramate has had mixed results in pediatric populations and there are concerns about it worsening psychiatric symptoms. One small open-label trial in youth showed a slowing of weight gain with amantadine. Melatonin and vitamin D have also been studied but have not demonstrated statistically significant impact on weight. Naltrexone-bupropion and phentermine for antipsychotic-induced weight gain have limited evidence for efficacy in adults but not in children or adolescents.
While second-generation antipsychotics are useful and effective medications, it is important to monitor closely for metabolic side effects including weight gain. As mentioned above, start by encouraging behavioral and lifestyle interventions and if needed, consider pharmacological options. At this juncture, metformin remains the most evidence-supported and safest options for antipsychotic-induced weight gain. GLP-1RAs and betahistine offer promise, but additional research in youth is needed before widespread clinical adoption in pediatric populations.
AUTHOR:
Dr. Kristen Kim, MD
Child, Adolescent and Adult Psychiatrist
Vista Hill Foundation