Shannon N. Saldaña

Codeine-related adverse drug reactions in children following tonsillectomy: a prospective study.

To prospectively determine factors associated with codeines adverse drug reactions (ADRs) at home in a large homogenous population of children undergoing outpatient tonsillectomy.

Hospitalized youth and child abuse: a systematic examination of psychiatric morbidity and clinical severity.

Many children and adolescents who require psychiatric hospitalization have been physically or sexually abused, yet the association between reported histories of abuse and the complexity and severity of mental illness among psychiatrically hospitalized youth is poorly described with regard to current inpatient psychiatric practice. We sought to determine the association between histories of abuse and psychiatric complexity and severity in psychiatrically hospitalized youth including comorbidity patterns, psychotropic medication use, reason for admission and length of hospitalization. A systematic chart review was performed on 1433 consecutive psychiatric hospitalizations of children and adolescents that occurred over a 10-month period. Children with a history of abuse were more likely to be diagnosed with multiple DSM-IV-TR disorders than non-traumatized children. A history of sexual abuse was associated with more medication use than in their non-traumatized peers and a higher likelihood of treatment with antipsychotic medications, both at admission and discharge. Physical and sexual abuse were independently associated with increased length of stays, with exposure to both physical and sexual abuse associated with a 2-day increase in duration of hospitalization compared to non-traumatized patients. The findings from this study draw attention to the adverse impact of abuse on psychiatric morbidity and complexity and suggest the need for trauma-informed treatment in psychiatric hospital settings.

Population pharmacokinetics of sirolimus in pediatric patients with neurofibromatosis type 1

Purpose: The narrow therapeutic index and large interpatient variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with neurofibromatosis type 1 (NF1). The objectives of this study were to estimate sirolimus clearance in a cohort of children with NF1 using data collected in a concentration-guided trial, to evaluate the effect of treatment duration on clearance and dose requirements, and to evaluate the association of sirolimus clearance with patient-specific factors, including age, weight, body surface area (BSA), race, and sex. Methods: Sirolimus concentration–time data were collected from an ongoing prospective trial in children with NF1. An iterative 2-stage Bayesian method was used for the PK parameter analyses. Results: Data from 44 patients with NF1 were included in the analyses. Mean age was 8.4 years (SD 4.5, range 3–18), and mean weight was 29.8 kg (SD 16.7, range 12–85.8). Mean sirolimus clearance was 11.8 L/h (SD 4.6, range 2.2–24.1), and the mean dose to obtain a target trough concentration of 10–15 ng/mL was 2.0 mg/m2 administered twice daily (SD 0.72, range 0.77–3.85). A nonlinear relationship between age and clearance was observed. Total body weight and BSA were strong predictors of sirolimus clearance (r2 = 0.67 and 0.65, respectively). Conclusions: Sirolimus clearance in children with NF1 is comparable with that in pediatric transplant patients. Clearance was most associated with body size parameters (BSA and total body weight) in children with NF1. When normalized for size, an age effect on clearance was observed in the youngest patients, most likely because of the maturational changes in drug absorption and metabolism. A mean dose of 2.0 mg/m2 twice a day was required for attainment of target trough concentrations of 10–15 ng/mL in children greater than 3 years of age who have NF1. The updated model will allow PK-guided individualized dosing of sirolimus in patients with NF1.

Population pharmacokinetic modeling of risperidone and 9-hydroxyrisperidone to estimate CYP2D6 subpopulations in children and adolescents

Aim: The study aims were to characterize risperidone and (±)-9-hydroxyrisperidone pharmacokinetic (PK) variability in children and adolescents and to evaluate covariate effects on PK parameters. Methods: Steady-state samples were drawn at predose, 1, 2, 4, and 7 hours postdose; cytochrome P450 2D6 (CYP2D6) genotypes were available for 28 subjects. A nonlinear mixed-effects model (NONMEM) modeled the PKs of risperidone and (±)-9-hydroxyrisperidone; covariates included age, weight, sex, and CYP2D6 phenotype. The model included 497 observations [risperidone (n = 163), (+) and (−)-9-hydroxyrisperidone (n = 334)] from 45 subjects aged 3–18.3 (mean 9.6 ± 3.7) years, weighing 16.8–110 (43 ± 20.2) kg. Results: A 1-compartment mixture model described risperidone and (±)-9-hydroxyrisperidone clearances for 3 CYP2D6 metabolizer subpopulations: extensive, intermediate, and poor. Weight significantly affected (±)-9-hydroxyrisperidone clearance. Clearance estimates in the mixture model were poor metabolizer 9.38 L/h, intermediate metabolizer 29.2 L/h, and extensive metabolizer 37.4 L/h. Conclusion: Active moiety [risperidone plus (±)-9-hydroxyrisperidone] PK variability and the covariate effects were better explained with the addition of metabolite PK parameters. This model may aid the development of individualized risperidone dosing regimens in children and adolescents.

Antipsychotic polypharmacy in children and adolescents at discharge from psychiatric hospitalization.

Antipsychotic polypharmacy―the use of more than one antipsychotic concomitantly—has increased in children and adolescents and may be associated with increased adverse effects, nonadherence, and greater costs. Thus, we sought to examine the demographic and clinical characteristics of psychiatrically hospitalized children and adolescents who were prescribed antipsychotic polypharmacy and to identify predictors of this prescribing pattern.

Treatment with Adjunctive N-Acetylcysteine in an Adolescent with Selective Serotonin Reuptake Inhibitor-Resistant Anxiety

elective serotonin reuptake inhibitors (SSRIs) are amainstay of psychopharmacologic treatment for pediatricanxiety disorders (Strawn et al. 2012); however, 20–35% of SSRI-treated youth with anxiety disorders do not achieve significantbenefit from these treatments (Walkup et al, 2008). Nonetheless,there is currently limited evidence for adjunctive pharmacologicinterventions in children and adolescents with who have notresponded to initial SSRI medications. Recently, however, severalstudies of anxiety-spectrum disorders in adults have noted increasedcentral glutamate concentrations, and glutamatergic hyperactivity isimplicated in the pathophysiology of anxiety disorders (Phan et al.2005). Among available glutamate modulators is the over-the-counter antioxidant, N-acetylcysteine (NAC), which is convertedinto cysteine and—through its action at the glial cysteine–glutamateantiporter—increases extrasynaptic glutamate and, in doing so,stimulates inhibitory metabotropic glutamate receptors and de-creases synaptic glutamate (Lafleur et al., 2006). This decrease insynaptic glutamate has been hypothesized to confer benefit in anx-iety treatment. Herein, we report a case of a 17-year-old adolescentboywithfunctionally-impairinggeneralizedanxietydisorder(GAD)and social phobia (SoP),who partially responded to high-dose ser-traline, but whose response was accentuated by adjunctive NAC.A. is a 17-year-old white boy with a history of GAD andgeneralized SoP. At initial outpatient presentation, A. describedpersistent fear of social situations, was preoccupied by perceivedevaluation by peers and social situations, and he avoided mostsocial situations, including school. He had demonstrated limitedimprovement in school avoidance and withdrawal from socialsituations, despite ongoing cognitive-behavioral psychotherapyand fluoxetine, which had been titrated to 20mg daily and report-edly worsened his anxiety. A. also described intense anxiety relatedto the future, a constant sense of inner tension and restlessness, andanxious ruminations that were associated with initial and middleinsomnia. Moreover, he described recurrent headaches in times ofanxiety, and secondary to his significant anxiety, A. had recentlyterminated his part-time employment at a local restaurant.Fluoxetine was discontinued and, over the next 8 weeks,sertraline monotherapy was initiated and titrated to 150mg daily,yielding a decrease in his anxiety. However, although there wassome improvement in his subjective anxiety, A. reported persistentsocial anxiety andhisClinicalGlobalImpressions-Severity(CGI-S)score remained a 5. At that time, adjunctive NAC was initiated(600mg capsules by mouth twice daily) and, over the next 4 weeks,A.experiencedadecreaseinhisanxietyandhisCGI-Sdecreasedtoa4. To target A.’s significant anxiety symptoms, NAC was increasedto 1200mg twice daily and, over the subsequent 4 weeks, he noted adecreaseinanxietyandbecameabletoattendseveralsocialactivitieswith friends at a local coffee shop, was less concerned about others’perceptionsofhim,andwasableto attendchurchandbeginapplyingfor a part-time job. A. also reported improvement in his anxiety-related insomnia, a decrease in his sense of inner tension and rest-lessness, and diminished somatic symptoms. At that time, his CGI-Shad decreased to 2, he reported that adjunctive NAC was welltolerated, and he denied any side effects.This case highlights the potential efficacy of adjunctive NAC(1200mg twice daily) in adolescents with anxiety disorders whohave experienced partial responses to SSRI pharmacotherapy. Theonset of action was rapid, with reduction of psychic and somaticanxiety symptoms; onset of efficacy occurred within 1 week of thetarget dose (1200mg twice daily), and the effect was sustained overthe treatment period. Importantly, NAC was well tolerated, as hasbeen the case in children with autism (Hardan et al. 2012), in ad-olescents with cannabis dependence (Gray et al. 2012), in adultswith trichotillomania (Grant et al. 2009), and when used adjunc-tively with SSRIs, in adults with SSRI-resistant anxiety disorders(Lafleur et al. 2006). Additional, prospective trials are urgentlyneeded to assess the potential role of glutamate modulators, such asNAC, in youth with anxiety disorders, including those who havehad partial responses to ‘‘first-line’’ psychopharmacologic andpsychotherapeutic interventions.DisclosuresDrs. Strawn and Saldan˜a disclosed no competing financial in-terests. Dr. Strawn has received research support from Eli Lilly,Shire, and the American Academy of Child & Adolescent Psy-chiatry; these are noted in the spirit of full disclosure and are notdirectly related to the work or results presented herein.References

Disinhibition as a side effect of treatment with fluvoxamine in pediatric patients with obsessive-compulsive disorder.

Selective serotonin reuptake inhibitors (SSRIs) are usually well tolerated in the pediatric population, and widely used in the treatment of obsessive-compulsive disorder (OCD). Of the 51 pediatric patients with obsessive-compulsive disorder seen in our outpatient clinic between January 2009 and July 2009, 3 of them developed behavioral disinhibition after treatment with fluvoxamine. These cases are described and discussed in relation to the use of CYP2D6 and CYP2C19 pharmacogenetic testing in patients treated with serotonin-selective reuptake inhibitors.

Nurses' Genetic/Genomics Competencies when Medication Therapy is Guided by Pharmacogenetic Testing: Children with Mental Health Disorders as an Exemplar

There is considerable variability in the effectiveness and toxicity of psychotropics used to treat mental health disorders in children and adolescents. Pharmacogenetic (PG) testing is beginning to be used to decrease the time it takes to reach therapeutic response and decrease the occurrence of adverse drug reactions in children and adolescents treated with psychotropics. This article reviews the pharmacogenetics literature and uses a clinical scenario to illustrate the essential genetic/genomics competencies pediatric nurses need to meet when providing care to patients whose medication therapy is being guided by PG testing.

Retrospective Review of the Relationship Between Weight Change and Demographic Factors Following Initial Depot Medroxyprogesterone Acetate Injection in Adolescents

BACKGROUND Depot medroxyprogesterone acetate (DMPA) is an effective (<1% annual failure rate) contraceptive administered by intramuscular injection every 3 months. DMPA is an increasingly popular contraceptive choice for adolescents, yet its use is associated with weight gain as well as subsequent nonadherence and long-term obesity-related diseases and mortality. Precise risk factors for DMPA-associated weight gain and the time periods of greatest weight increases have not been reported. Knowledge of these factors may prompt individualized counseling and proactive approaches to minimizing weight gain during DMPA treatment. OBJECTIVE This study evaluated the relationship between weight change at 10 to 14 weeks post-DMPA initiation and race, baseline weight, and gynecologic age (age at DMPA initiation minus age at menarche) in female adolescents. METHODS Data for baseline and 10 to 14 weeks post-DMPA initiation were obtained via retrospective chart review of 115 female adolescents treated at Cincinnati Childrens Hospital Medical Center. Descriptive statistics, 2-tailed t tests, and a multivariable linear regression model were used to evaluate weight gain and potentially associated characteristics. RESULTS A total of 29 of 115 patients (25%) were excluded from the analysis owing to first post-DMPA initiation visit occurring later than 14 weeks, no recorded weight, and/or no documented age of menarche. For the 86 patients (75%) included in the analysis (study cohort), the mean (SD) baseline weight was 60.4 (14.0) kg (range, 36.4-114.8 kg), the mean (SD) age at initiation was 15.5 (1.3) years, the mean (SD) gynecologic age was 3.8 (1.6) years, and 83% of DMPA-treated adolescents were of black race. There was no significant difference in the mean weight change during the 10 to 14 weeks post-DMPA initiation by race; 0.19 kg for black patients versus -0.97 kg for non-black patients (P = 0.16; 95% CI of the difference, -0.49 to 2.81). For black patients, there was no significant difference in the mean weight change by gynecologic age (P = 0.58; 95% CI, -0.69 to 1.22). A multivariable linear regression model demonstrated that baseline weight (P = 0.60), race (P = 0.07), and gynecologic age (P = 0.88) were not significantly associated with weight change during the 10 to 14 weeks following DMPA initiation. CONCLUSION In this study cohort, race, gynecologic age, and baseline weight were not associated with weight gain 10 to 14 weeks following initiation of DMPA.

Drug-metabolizing enzyme genotypes and aggressive behavior treatment response in hospitalized pediatric psychiatric patients.

OBJECTIVE The aim of this study was to examine the association between the CYP2D6 and CYP2C19 genotype-predicted combined phenotypes and short-term measures of psychotropic efficacy and toxicity. METHODS A rater-blinded, retrospective genotype association design examined a cohort of hospitalized pediatric psychiatric patients genotyped for CYP2D6 and CYP2C19 as part of clinical care. These combined genotypes were used to predict a combined phenotype. The primary efficacy outcome measure was the behavior intervention score (BIS), a function of the number of recorded timeouts/seclusions, therapeutic holds, and physical restraints. Drug tolerability was defined as the total number of recorded adverse drug reactions. RESULTS Primary analysis was performed on 279 pediatric patients taking CYP2D6- or CYP2C19- dependent psychotropics. Combined phenotype was associated with BIS (p = 0.01) and number of adverse drug reactions (p = 0.03). Combined poor metabolizers treated with psychotropics had the lowest BIS (highest efficacy) and the highest number of adverse drug reactions. Combined ultrarapid metabolizers had the highest BIS (lowest efficacy) and the lowest number of adverse drug reactions. CONCLUSION Common variants in CYP2D6 and CYP2C19 are associated with the short-term efficacy and tolerability of psychotropic medications in hospitalized pediatric patients.