The Burden of Antipsychotic-Induced Weight Gain and Metabolic Syndrome in Children

Abstract

Antipsychotic medications are critical to child and adolescent psychiatry, from the stabilization of psychotic disorders like schizophrenia, bipolar disorder, and psychotic depression to behavioral treatment of autism spectrum disorder, tic disorders, and pediatric aggression. While effective, these medications carry serious risk of adverse events-most commonly, weight gain and cardiometabolic abnormalities. Negative metabolic consequences affect up to 60% of patients and present a major obstacle to long-term treatment. Since antipsychotics are often chronically prescribed beginning in childhood, cardiometabolic risk accumulates. An increased susceptibility to antipsychotic-induced weight gain (AIWG) has been repeatedly documented in children, particularly rapid weight gain. Associated cardiometabolic abnormalities include central obesity, insulin resistance, dyslipidemia, and systemic inflammation. Lifestyle interventions and medications such as metformin have been proposed to reduce risk but remain limited in efficacy. Furthermore, antipsychotic medications touted to be weight-neutral in adults can cause substantial weight gain in children. A better understanding of the biological underpinnings of AIWG could inform targeted and potentially more fruitful treatments; however, little is known about the underlying mechanism. As yet, modest genetic studies have nominated a few risk genes that explain only a small percentage of the risk. Recent investigations have begun to explore novel potential mechanisms of AIWG, including a role for gut microbiota and microbial metabolites. This article reviews the problem of AIWG and AP metabolic side effects in pediatric populations, proposed mechanisms underlying this serious side effect, and strategies to mitigate adverse impact. We suggest future directions for research efforts that may advance the field and lead to improved clinical interventions.

Keywords: adverse drug effects; antipsychotic-induced weight gain; antipsychotics; child psychiatry; metabolic syndrome; pediatrics.

Figure 1

The associated burden of pediatric antipsychotic treatment. Antipsychotic use is associated with weight gain, increased fasting lipids (total cholesterol, LDL, and triglyceride levels), and impaired glucose tolerance in pediatric patients. Subsequently, this population is at an increased risk of obesity, metabolic syndrome and type 2 diabetes. Although pediatric patients are more vulnerable to these adverse side effects, they are less likely to have their metabolic parameters monitored during AP treatment.

Figure 2

Possible mechanisms of antipsychotic adverse metabolic effects. The energy homeostasis pathway is complex and provides numerous possible mechanisms that might explain AP-related weight gain and metabolic effects. Arrow at end of line indicates activation of pathway and perpendicular bar denotes inhibition. Neuroendocrine signaling molecules are bolded. Potential AP inputs are italicized and represented by dotted lines. ARC, arcuate nucleus; LH, lateral hypothalamus; NPY, neuropeptide Y; AgRP, agouti-related peptide; POMC, pro-opiomelanocortin; NPYR, neuropeptide Y receptor; MC4R, Melanocortin 4 Receptor; α-MSH, alpha-Melanocyte-stimulating hormone.

Figure 3

(A,B) Clinical guideline and decision support for the assessment, prevention, and treatment of metabolic adverse effects of antipsychotic medications in youth. Adapted from the American Academy of Child and Adolescent Psychiatry (7) and American Psychiatric Association and American Diabetes Association Guidelines (70). (A) Initial Assessment and Plan. (B) Follow-up Assessment and Plan.