Of approximately one million US children and adolescents, roughly 1% are prescribed second-generation antipsychotics (SGAs). These medications routinely breach the FDA’s level of concern of >7% body weight gain. The worst offenders are olanzapine, quetiapine, and risperidone; lurasidone and ziprasidone are of less concern (Maayan L and Correll CU, J Child Adolesc Psychopharmacol 2011;21(6):517–535). This article examines the efficacy and safety of using off-label medications, such as metformin, to manage this side effect.

Metformin

Metformin, approved for type II diabetes, is the best-studied treatment for metabolic side effects of SGAs. Metformin increases insulin sensitivity in liver and muscle and decreases hepatic glucose production and intestinal glucose absorption. The large, detailed IMPACT study of metformin in children and adolescents on SGAs showed that while metformin stopped ongoing weight gain, it led to minimal weight loss and metabolic improvement over the course of the study. After 24 weeks, metformin patients lost 0.4 pounds, while control patients gained 8.5 pounds (Correll CU et al, World Psychiatry 2020;19(1):69–80).

Cautions

The most common side effect of metformin in the IMPACT study was mild to moderate gastrointestinal distress, with symptoms such as decreased appetite, abdominal pain, nausea and vomiting, diarrhea, and encopresis. These occurred early, were mostly transient, and were manageable by slowing titration or using a lower dose of metformin. Interestingly, metformin was associated with fewer problems with aggression, hostility, anger, irritability, and impulsiveness. The authors postulated this could be due to feeling less “hangry” or having better glucose homeostasis. Rare potential side effects, not observed in this study, are low serum vitamin B12 level and metabolic acidosis. The only absolute contraindications to the use of metformin are chronic kidney disease and low glomerular filtration rate (GFR).

When to start metformin

While metformin can prevent future weight gain, it is unlikely to decrease existing weight. If a child is already overweight for their height or if you are starting an antipsychotic with a high risk of weight gain, start metformin with the antipsychotic. If families resist starting two medications at once, check your patient’s height and weight, and start metformin if their weight begins to rise at a rate greater than expected based on their growth.

How to prescribe metformin

Check kidney function prior to starting metformin. Metformin is contraindicated if the GFR is <30, due to increased risk of lactic acidosis. It is safest to have a GFR >60. Serum creatinine and serum B12 level should be checked annually if kidney function is normal (eGFR >60), and more frequently if eGFR is 45–60. If eGFR is <45, it is safest to stop metformin.

Titrate slowly to minimize gastrointestinal side effects. We recommend following the schedule used in the IMPACT trial.

For youth < 50 kg:

• Prescribe 250 mg at dinner for one week
• Increase to 250 mg at breakfast and dinner for one week
• Increase by 250 mg/week to a maximum of 500 mg twice daily

For youth 50–70 kg:

• Prescribe 250 mg at dinner for one week
• Increase to 250 mg at breakfast and dinner for one week
• Increase by 250 mg/week to a maximum of 1000 mg twice daily

For youth >70 kg:

• Prescribe 500 mg at dinner for one week
• Increase to 500 mg at breakfast and dinner for one week
• Increase by 500 mg/week to a final dose of 1000 mg BID

In addition to metformin, other medications have been tried in this context, and we cover them in more detail below.

Topiramate

Topiramate also prevents weight gain better than it reduces weight (Zheng W et al, Acta Psychiatr Scand 2016;134(5):385–398). In a meta-analysis of randomized controlled trials (RCTs) of adjunctive topiramate for schizophrenia, 22 out of 26 trials showed topiramate led to a significantly lower body weight of 2.75 kg (weighted mean difference).

An 11-week open trial in adolescents with medication-induced weight gain titrated topiramate to 150 mg/day, giving a mean weight loss of 2.62 kg (Tramontina S, J Child Adolesc Psychopharmacol 2007;17(1):129–134). A meta-analysis of RCTs of topiramate in the treatment of obesity in adults found that, at doses of 96–200 mg/day, trials of <28 weeks led to a weight loss of 4.11 kg, and trials of >28 weeks led to a weight loss of 6.58 kg (Kramer CK, Obes Rev 2011;12(5):e338–e347).

Side effects of topiramate include oligohidrosis (decreased sweating) and hyperthermia during exercise, metabolic acidosis, word-finding problems, and cognitive impairment (which might be avoided with slow titration by 25 mg/week). Other side effects include a two- to four-fold increased risk of kidney stones, paresthesias, acute myopia with angle-closure glaucoma, and visual field defects.

How to prescribe topiramate

Start topiramate at 25 mg per day, increasing by 25 mg every week as tolerated to a maximum dose of 150–200 mg/day. Higher doses are not more efficacious based on the (scant) data available.

What about combining metformin and topiramate?

The combination of metformin and topiramate was safe and effective in a recent case report of an 8-year-old with ­antipsychotic-associated weight gain (Nagy LR et al, J Child Adolesc Psychopharmacol 2022;32(1):72–76). Zheng and colleagues (2016) also suggest considering combining metformin and topiramate when monotherapy is insufficient. However, since both metformin and topiramate can cause metabolic acidosis, check labs every few weeks until you reach steady dosages. Then recheck after dosage adjustments or significant weight loss, as the latter also increases the relative dosage.

Glucagon-like peptide (GLP-1) agonists

GLP-1 agonists are almost all weekly injectable medications—with the exception of semaglutide (Rybelsus), which is used orally for adults with diabetes. They are FDA approved for use in type II diabetes and weight management. GLP-1 agonists decrease appetite, delay gastric emptying (which promotes satiety), and increase visceral and intra-organ lipolysis.

For children and teens, liraglutide (Victoza, Saxenda) is approved for ages 10 and up for type II diabetes, and ages 12 and up for weight management. It is expensive: Saxenda costs $1,628/month retail, $1,315/month with GoodRx. Typical prior authorization criteria include BMI >30 without comorbid conditions, or BMI >27 with comorbid conditions, and failure to lose 5% of body weight after three months in a weight loss program.

GLP-1 agonists are contraindicated in patients with a history of pancreatitis, medullary thyroid cancer (including a family history), and multiple endocrine neoplasia type II. They should be used with caution in patients with renal insufficiency, and they can increase the risk of gallbladder disease (He L et al, JAMA Intern Med 2022; Epub ahead of print).

Despite the allure of GLP-1 agonists, we do not yet have many data on their use in antipsychotic-associated weight gain, although case studies report good effects in young teens with Prader-Willi syndrome (Goldman VE et al, J Clin Med 2021;10(19):4540).

Stimulants

You may be tempted to use stimulants to prevent antipsychotic-associated weight gain, but in fact studies have shown lack of efficacy (Penzner JB et al, J Child Adolesc Psychopharmacol 2009;19(5):563–573).

What about Lybalvi?

This combination of olanzapine and samidorphan (an opioid antagonist) was recently approved to treat adults with bipolar disorder and schizophrenia and is purported to cause less weight gain; however, it has not been studied in children.

CARLAT VERDICT

When you need to use SGAs, consider starting with meds less likely to cause weight gain, such as lurasidone or ziprasidone. If you are using a different SGA, think about starting metformin simultaneously, especially for patients with BMI >25. For patients with BMI >30, consider starting a GLP-1 agonist with the SGA