Leptin gene -2548G/A variants predict risperidone-associated weight gain in children and adolescents

Abstract

Objective: As the use of atypical antipsychotics in children and adolescents has increased, concerns have been raised about their long-term safety. We aimed to investigate the association between risperidone-induced weight gain, leptin concentration, and the leptin gene (LEP) -2548G/A variants in youths.

Methods: Medically healthy 7- to 17-year-old children and adolescents, in extended naturalistic treatment with risperidone, were recruited through pediatric psychiatry clinics. Anthropometric measures and laboratory testing were conducted. Growth and medication history was obtained from the medical record. The effect of the LEP genotypes on leptin concentration and on the slopes of the weight and body mass index (BMI) Z-score curves before and after the onset of risperidone treatment was investigated .

Results: In 74 individuals, chronically treated with risperidone, the A allele was associated with higher leptin concentration at low weight and BMI Z-scores. There was no effect of the LEP genotypes on weight or BMI Z-scores before risperidone was started. Afterwards, however, the A-allele carriers showed a steeper rate of increase in weight and BMI Z-scores. As a result, the GG-genotype carriers were 2.5 times less likely to be overweight/obese (i.e. having a BMI above the 85th percentile). This genetic effect on risperidone-associated weight gain did not extend to weight loss related to psychostimulants.

Conclusion: The LEP - 2548G/A variants seem to moderate the weight-altering effect of risperidone but not psychostimulants. This may be related to genetic differences in tissue sensitivity to leptin, resulting in differential body composition.

Figure 1

After adjusting for BMI z score, age, gender, and stage of sexual development, the LEP -2548G/A genotype interacted with BMI z score to predict leptin concentration (log transformed). Thus, at lower BMI z scores, the A allele carriers had significantly higher leptin concentrations.

Figure 2

Before risperidone was started, there was no effect of the LEP -2548G/A genotype on weight z score. Afterwards, however, weight z score increased faster in the A allele carriers than in the GG genotype group. Weight z scores are adjusted for baseline weight z score and the dose of methylphenidate/kg of body weight.

Figure 3

Neither before nor after the onset of psychostimulant treatment did either of the LEP -2548G/A genotype groups have an effect on the change in weight z score. As expected, weight z score gradually decreases after psychostimulants (MPH) are started.