Metformin-Induced Type 1 Hypersensitivity in a Child with Antipsychotic-Induced Weight Gain

To The Editor:

Metformin is a biguanide derivative oral antihyperglycemic. It is a first-line medication in the treatment of type 2 diabetes. More recently, it has been used to counteract weight gain associated with atypical antipsychotics in the pediatric population (Klein 2006; Arman et al. 2008). Type 1 hypersensitivity is an immediate allergy reaction in response to a specific allergen. Pathophysiology includes production of IgE antibodies, sensitized mast cells, and basophils. The subsequent release of histamine causes vasodilation. Here, we describe a case of a 10-year-old boy who developed a type 1 hypersensitivity reaction after his first dose of metformin 500 mg started to treat metabolic syndrome associated with successful use of risperidone as an antimanic agent.

Case Report

A 10-year-old boy was diagnosed 3 years previously with type I bipolar disorder after completing a Child Schedule of Affective Disorders and Schizophrenia Present and Lifetime version administered in the context of a research study by a physician board certified in pediatrics, adult psychiatry, and child/adolescent psychiatry. After diagnosis, risperidone was initiated as an antimanic agent. Family indicated significantly reduced bipolar symptoms, including reduced irritable and euphoric mood as well as aggression. However, shortly after initiation, family also noted side effects, including markedly increased appetite and request for nighttime snacks.

Over 2 years, risperidone was titrated to a total daily dose of 1.5 mg and he continued to have beneficial antimanic effect. However, despite attempts to encourage daily mild/moderate exercise and decreased calorie density of meals and snacks, the patient gained 40 pounds and his body mass index (BMI) increased from the 87th to the 97th percentile.

After reviewing the risks, benefits, and alternatives, the family consented to start metformin. However, within 10 minutes of the first 500 mg metformin dose, the family noticed new-onset urticaria and facial flushing. Parents reported additional dermatological manifestations, including raised, erythemic, and pruritic patches confined to the left antecubital fossa. Parents administered diphenhydramine 25 mg immediately, and then a second dose 20 minutes later. Within 30 minutes, the urticaria and facial flushing subsided without need for higher level of care or additional treatments.

After the parents reported the rash, we suggested they stop metformin. During 2 months of follow-up with stable risperidone dose and no metformin, the patient has had no recurrence of this reaction, but his BMI is 96.7th percentile.

Discussion

In this case, the sudden onset of urticaria and facial flushing with the introduction of metformin is believed to be the result of a drug reaction. Metformin has well-established GI side effects including diarrhea. In addition to this, a series of case reports indicate metformin-induced cutaneous reactions, including leukocytoclastic vasculitis, psoriatic drug eruption, lichenoid reaction of the oral muscosa, and rosacea-like facial rash (Koca et al. 2003; Wiwanitkit 2011; Mumoli et al. 2014; Zaïem et al. 2014). To date, metformin allergy is particularly rare with only mild erythema reported in sensitive patients along with one case study of angioedema (Atik et al. 2013).

The world obesity epidemic—both in the general child population and in children on atypical antipsychotics, specifically—is a complex, multifactorial problem. Clinicians are increasingly employing similarly multilevel treatment strategies, which include oral hypoglycemic agents (World Health Organization 2016). Although appropriately prescribed atypical antipsychotic medications can help a variety of psychiatric conditions, weight gain and adverse metabolic effects are well-established risks. This is particularly concerning in children and adolescents, where if helpful, such antipsychotic agents may be used for years. As a result, many providers have sought interventions for antipsychotic-induced weight gain. Metformin is the most thoroughly investigated agent to reduce such antipsychotic-induced weight gain, with consistent weight loss among adults (Fiedorowicz et al. 2012). Two studies have looked at metformin use in child populations. A large, randomized controlled trial (RCT) demonstrated an average loss of 4.1 kg relative to placebo (Klein et al. 2006), whereas a smaller RCT indicated no significant differences in metformin verses placebo groups as both lost significant weight and BMI (Arman et al. 2008). Metformin is proposed to act in three ways: (1) inhibiting hepatic gluconeogenesis and glycogenolysis, (2) increasing muscle insulin sensitivity, and (3) delaying intestinal glucose absorption (Metformin 2016).

Although the risk of allergic reaction to metformin is listed in prescribing information, given its increasing and often successful use to treat antipsychotic agent-associated weight gain, our case highlights the need for: (1) greater provider awareness and patient education about the potential for metformin-induced type 1 hypersensitivity reaction, (2) greater systemic surveillance for such events, and (3) guidelines about how to handle such reactions, including considerations of readministering metformin verses relative risk versus benefit of other oral hypoglycemic agents in children for this indication.