title: Predictors of risperidone and 9-hydroxyrisperidone serum concentration in children and adolescents.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Psychiatry, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. chadi-calarge@uiowa.edu
authors.forename: Chadi Albert
authors.initials: CA
authors.lastname: Calarge
authors.forename: Del D
authors.initials: del D
authors.lastname: Miller
mesh_terms: D000293:Adolescent; D000375:Aging; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D015992:Body Mass Index; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000188:drug therapy / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D001523:Mental Disorders / Q000150:complications / Q000188:drug therapy; D000068882:Paliperidone Palmitate; D019338:Polypharmacy; D011618:Psychotic Disorders / Q000188:drug therapy / Q000235:genetics; D011743:Pyrimidines / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018967:Risperidone / Q000009:adverse effects / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D012737:Sex Factors; D046468:Sexual Development / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D007555:Isoxazoles; D011743:Pyrimidines; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone; D000068882:Paliperidone Palmitate