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1.  Iron Deficiency in Pediatric Patients in Long-Term Risperidone Treatment 
Atypical antipsychotics, increasingly used in children and adolescents, modulate brain dopamine. Iron plays a critical role in dopaminergic signaling. Therefore, we explored whether body iron status is related to psychiatric symptom severity, treatment response, and tolerability following extended antipsychotic therapy.
Between November 2005 and August 2009, medically healthy 7–17-year-old risperidone-treated participants enrolled in a cross-sectional study examining the long-term safety of this antipsychotic. Anthropometric measurements were obtained. Psychiatric symptom severity and dietary intake were assessed. Serum ferritin, transferrin receptor, and prolactin concentrations were measured. Linear multivariable regression analysis tested the association among body iron, symptom severity, the dose of risperidone and psychostimulants, and serum prolactin concentration.
The sample consisted of 115 patients (87% males) with a mean (±SD) age of 11.6 (±2.8) years. The majority had externalizing disorders, and they had taken risperidone for 2.4 (±1.7) years. Body iron was low, with 45% having iron depletion and 14% having iron deficiency. Iron status was inversely associated with weight gain during risperidone treatment and with interleukin-6. Body iron was neither associated with psychiatric symptom severity nor with the daily dose of risperidone and psychostimulants. It was, however, inversely associated with prolactin concentration, which was nearly 50% higher in the iron-deficient group.
Iron depletion and deficiency are prevalent in children and adolescents chronically treated with risperidone. Iron deficiency accentuates the antipsychotic-induced elevation in prolactin. Future studies should confirm this finding and investigate the potential benefit of iron supplementation in antipsychotic-treated patients.
PMCID: PMC3609616  PMID: 23480322
2.  Predictors of Risperidone and 9-Hydroxyrisperidone Serum Concentration in Children and Adolescents 
Little is known about risperidone metabolism in a clinical sample, where polypharmacy is common. Such knowledge is important since several of its side effects are dose dependent.
Medically healthy patients aged 7 to 17 years old treated with risperidone for at least 6 months were enrolled. Trough serum risperidone and 9-hydroxyrisperidone concentrations were measured.
One hundred seven participants (92% males) were recruited, representing a heterogenous clinical group with attention-deficit/hyperactivity disorder, disruptive behavior disorders, pervasive developmental disorders, anxiety disorders, mood disorders, tic disorders, or psychotic disorders. Risperidone had been used at a mean dose of 0.03 mg/kg, for a mean 2.5 years, predominantly to treat irritability and aggression. Cytochrome CYP2D6 inhibitors were divided into prominent (fluoxetine, bupropion, and lamotrigine), intermediate (sertraline), and weak inhibition groups (citalopram or escitalopram). The concentrations of risperidone and its metabolite were strongly associated with the dose of risperidone and time since the last dose and, to a lesser extent, with male sex. In addition, risperidone concentration increased with pubertal stage (p < 0.05), while body mass index z-score (p = 0.001) predicted a higher 9-hydroxyrisperidone concentration. The use of CYP2D6 inhibitors was much more strongly associated with risperidone concentration (p < 0.0001) than with its metabolite's (p = 0.06).
In chronically treated youths, the metabolism of risperidone depends on the stage of sexual development, whereas that of 9-hydroxyrisperidone varies with body fat. Moreover, CYP2D6 inhibitors more strongly affect risperidone metabolism than that of its metabolite. The clinical implications of these findings, in relation to efficacy and tolerability, deserve further investigation.
PMCID: PMC3080754  PMID: 21486167
3.  Correlates of weight gain during long-term risperidone treatment in children and adolescents 
Most clinical trials of antipsychotics in children are brief, failing to address their long-term safety, particularly when taken concurrently with other psychotropics. This hypothesis-generating analysis evaluates potential correlates of weight gain in children receiving extended risperidone treatment.
Medically healthy 7–17 year-old patients treated with risperidone for six months or more were enrolled. Anthropometric measurements were conducted. Developmental and medication history was obtained from the medical record. Information related to birth weight, dietary intake, physical activity, and parental weight was collected. Mixed regression analyses explored the contribution of various demographic and clinical factors to age- and sex-adjusted weight and body mass index (BMI) z scores over the treatment period.
The sample consisted of 110 patients (89% males) with a mean age of 11.8 years (sd = 2.9) upon enrollment. The majority had an externalizing disorder and received 0.03 mg/kg/day (sd = 0.02) of risperidone, for 2.5 years (sd = 1.7), to primarily target irritability and aggression (81%). Polypharmacy was common with 71% receiving psychostimulants, 50% selective serotonin reuptake inhibitors (SSRIs), and 32% α2-agonists. Weight and BMI z score were positively correlated with baseline weight at the start of risperidone, treatment duration, and the weight-adjusted dose of risperidone but inversely associated with the weight-adjusted dose of psychostimulants and the concurrent use of SSRIs and α2-agonists. The effect of risperidone dose appeared to attenuate as treatment extended while that of psychostimulants became more significant. The rate of change in weight (or BMI) z score prior to and within the first 12 weeks of risperidone treatment did not independently predict future changes neither did birth weight, postnatal growth, dietary intake, physical activity, or parental weight.
This comprehensive analysis exploring correlates of long-term weight (or BMI) change in risperidone-treated youths revealed that pharmacotherapy exerts significant but complex effects.
Trial Registration
Not applicable.
PMCID: PMC3489823  PMID: 22643087
Child; Adolescent; Weight gain; Obesity; Antipsychotics; Risperidone; Predictors
4.  A Cross-sectional Evaluation of the Effect of Risperidone and Selective Serotonin Reuptake Inhibitors on Bone Mineral Density in Boys 
The aim of the present study was to investigate the effect of risperidone-induced hyperprolactinemia on trabecular bone mineral density (BMD) in children and adolescents.
Medically healthy 7–17yo males chronically treated, in a naturalistic setting, with risperidone were recruited through child psychiatry outpatient clinics between November 2005 and June 2007. Anthropometric measurements and laboratory testing were conducted. Developmental and treatment history was obtained from the medical record. Volumetric BMD of the ultra-distal radius was measured using peripheral quantitative computerized tomography and areal BMD of the lumbar spine was estimated using dual energy X-ray absorptiometry.
Hyperprolactinemia was present in 49% of 83 boys (n=41) treated with risperidone for an average of 2.9 years. Serum testosterone concentration increased with pubertal status but was not affected by hyperprolactinemia. As expected, bone mineral content and BMD increased with sexual maturity. After adjusting for the stage of sexual development, height and BMI Z-scores, serum prolactin was negatively associated with trabecular volumetric BMD at the ultra-distal radius (p<0.03). Controlling for relevant covariates, we also found treatment with selective serotonin reuptake inhibitors (SSRIs) to be associated with lower trabecular BMD at the radius (p=0.03) and BMD Z-score at the lumbar spine (p<0.05). These findings became more marked when the analysis was restricted to non-Hispanic Caucasians. Of 13 documented fractures, only two occurred after risperidone and SSRIs were started and none in patients with hyperprolactinemia.
This is the first study to link risperidone-induced hyperprolactinemia and SSRI treatment to lower BMD in children and adolescents. Future research should evaluate the longitudinal course of this adverse event to determine its temporal stability and whether a higher fracture rate ensues.
PMCID: PMC2845988  PMID: 20331935

Results 1-4 (4)