Suicidality in psychiatrically hospitalized children and adolescents: Demographics, treatment, and outcome.

BACKGROUND: Despite the high prevalence of suicidality in psychiatrically hospitalized youth, its risk factors and impact on inpatient psychopharmacologic treatment are unknown. We identified characteristics associated with suicidality in psychiatrically hospitalized youth and determined the association of suicidality with subsequent psychopharmacologic interventions. METHODS: Medical records from consecutive psychiatric admissions to a large, acute care, urban, pediatric hospital were analyzed retrospectively (N = 1,309). Demographic, clinical, and treatment-related features of suicidal and nonsuicidal youth were characterized. Logistic regression identified predictors of suicidality, and multiple comparison analyses evaluated the association between suicidality and changes to antidepressant prescribing during inpatient course. RESULTS: Compared with nonsuicidal patients, inpatients who were suicidal were more likely to have a mood disorder or posttraumatic stress disorder, as well as Cannabis and alcohol use, were more commonly girls, and at least 13 years of age (all P ≤ .05). Hospitalization was shorter for suicidal patients, was more likely to be associated with antidepressant treatment (P ≤ .001), and among suicidal patients prescribed antidepressants at the time of admission, was associated with a greater likelihood of changing antidepressant treatment compared with nonsuicidal inpatients (P ≤ .05). CONCLUSIONS: These findings reveal differences between suicidal and nonsuicidal psychiatrically hospitalized youth and suggest that suicidality is associated with specific pharmacologic treatment approaches within this population.

Sexual abuse is associated with obese children and adolescents admitted for psychiatric hospitalization.

OBJECTIVE: To determine the relationship between a history of child abuse and obesity among children admitted for psychiatric hospitalization. STUDY DESIGN: The charts of 1434 youth consecutively admitted to an inpatient psychiatric facility during a 10-month period were retrospectively analyzed. Rates of physical and sexual abuse, as well as other factors believed to increase the risk of obesity, were compared between children whose body mass index (BMI) percentiles were between 5 and 80 and whose BMI percentiles were >85. RESULTS: After correcting for age, race, gender, and antipsychotic usage, we found that a reported history of sexual abuse was associated with increased probability of being overweight/obese (BMI percentile 85-99) compared with being of typical BMI (aOR 1.41). Reported physical abuse neither increased the risk of obesity nor moderated the association between sexual abuse and increased weight. Antipsychotic treatment and female gender also were associated with increased BMI percentiles, with antipsychotic usage being the only variable associated with increased risk of a BMI percentile >99. CONCLUSIONS: Among youth with significant psychiatric illness, a history of sexual abuse increases the risk of being overweight or obese, an association that warrants further study regarding the temporal relationship between sexual abuse and obesity and may inform future obesity prevention and intervention programs in children.

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/m 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 (r = 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/m 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.

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.

Consumer satisfaction with National Alliance on Mental Illness written medicine information.

INTRODUCTION: Written medicine information (WMI) is a collection of facts for a specific medication, and it helps facilitate patient understanding of medication therapy. The primary objective of this study was to assess consumer satisfaction with National Alliance on Mental Illness (NAMI) WMI. A secondary objective was to assess health care professional satisfaction. METHODS: National Alliance on Mental Illness WMI and surveys were offered to consumers, health care professionals, and trainees at 3 treatment centers with psychiatric services. All adults who received medication counseling were eligible for inclusion. Survey responses were evaluated using descriptive statistics. RESULTS: Most consumers (82.4%) and providers (74.5%) reported overall satisfaction with NAMI WMI. Consumers were least satisfied with information on how to manage unwanted effects, drug-drug interactions, and readability (9.5%, 14.9%, 41.9% dissatisfaction). DISCUSSION: Evaluation and feedback from consumers and health care professionals may influence decisions to refine NAMI WMI to meet consumer needs.

Temperature and 3,4-methylenedioxymethamphetamine alter human serotonin transporter-mediated dopamine uptake.

Although studies have suggested that dopamine can be transported by serotonin transporters (SERTs), such activity has not been characterized at the cloned SERTs. Dopamine and serotonin uptake by human SERT expressed in HEK-293 cells was compared at 37 and 40 degrees C. Elevated temperature was found to alter serotonin transport, but had no significant effect on dopamine transport. These effects led to a 10-fold increase in the serotonin:dopamine transport ratio reflecting an increased preference of SERTs for dopamine as opposed to serotonin at the higher temperature. The effects of 3,4-methylenedioxymethamphetamine (MDMA) on SERT-mediated dopamine transport were also evaluated by pre-incubating SERT-expressing cells with MDMA. The presence of intracellular MDMA caused a decrease in [3H]dopamine uptake but had no effect on [3H]serotonin transport suggesting that intracellular MDMA may be capable of inhibiting transporter function.

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.

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

STUDY OBJECTIVE: 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. DESIGN: Retrospective medical record review. SETTING: The inpatient psychiatric unit of a large, acute care, urban children's hospital. PATIENTS: One thousand four hundred twenty-seven children and adolescents who were consecutively admitted and discharged between September 2010 and May 2011. MEASUREMENTS AND MAIN RESULTS: At discharge, 840 (58.9%) of the 1427 patients were prescribed one or more antipsychotics, and 99.3% of these received second-generation antipsychotics. Of these 840 patients, 724 (86.2%) were treated with antipsychotic monotherapy, and 116 (13.8%) were treated with antipsychotic polypharmacy. Positive correlations with antipsychotic polypharmacy were observed for placement or custody outside the biological family; a greater number of previous psychiatric admissions; longer hospitalizations; admission for violence/aggression or psychosis; and intellectual disability, psychotic, disruptive behavior, or developmental disorder diagnoses. Negative correlations with antipsychotic polypharmacy included admission for suicidal ideation/attempt or depression, and mood disorder diagnoses. Significant predictors of antipsychotic polypharmacy included admission for violence or aggression (odds ratio [OR] 2.76 [95% confidence interval (CI) 1.36-5.61]), greater number of previous admissions (OR 1.21 [95% CI 1.10-1.33]), and longer hospitalizations (OR 1.08 [95% CI 1.04-1.12]). In addition, diagnoses of intellectual disability (OR 2.62 [95% CI 1.52-4.52]), psychotic disorders (OR 5.60 [95% CI 2.29-13.68]), and developmental disorders (OR 3.18 [95% CI 1.78-5.65]) were predictors of antipsychotic polypharmacy. CONCLUSION: Certain youth may have a higher likelihood of being prescribed antipsychotic polypharmacy, which should prompt careful consideration of medication treatment options during inpatient hospitalization. Future examinations of the rationale for combining antipsychotics, along with the long-term safety, tolerability, and cost effectiveness of these therapies, in youth are urgently needed.

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

OBJECTIVES/HYPOTHESIS: To prospectively determine factors associated with codeine's adverse drug reactions (ADRs) at home in a large homogenous population of children undergoing outpatient tonsillectomy. STUDY DESIGN: Prospective, genotype blinded, observational study with a single group and repeated ADR measures documented by parents at home. METHODS: A total of 249 children 6 to 15 years of age scheduled for tonsillectomy were enrolled. The primary outcome was number of daily codeine-related ADRs. We examined the number and type of ADR by race and by days and further modeled factors potentially associated with ADR risk in a subcohort of white children. Sedation following a dose of codeine was a secondary outcome measure. Parents recorded their children's daily ADRs and sedation scores during postoperative days (POD) 0 to 3 at home. RESULTS: Diaries were returned for 134 children, who were given codeine. A total of 106 (79%) reported at least one ADR. The most common ADRs were nausea, lightheadedness/dizziness for white children and nausea, and vomiting for African American children. In a subcohort of white children ≤ 45 kg, increased ADR risk was associated with the presence of one or more full function CYP2D6 alleles (P < 0.001), POD (P < 0.001), and sex (P = 0.027). Increased pain intensity (P = 0.009) and PODs 0 and 1 (P = 0.001) contributed to a higher sedation risk. Neither obstructive apnea nor predicted CYP2D6 phenotype were associated with sedation risk. CONCLUSIONS: Our results provide evidence that multiple factors are associated with codeine-related ADRs and support the FDA recommendation to avoid codeine's routine use following tonsillectomy in children.

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 Children's 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.

Characteristics of successful recruitment in prospective pediatric pharmacogenetic studies.

BACKGROUND: There is a need to explore feasible means of accruing an appropriate study cohort to help fill the knowledge gap between pharmacogenetic contributions to drug response and clinical application in the pediatric population. OBJECTIVES: The aim of this study was to identify factors affecting recruitment of eligible subjects in pharmacogenetic studies at a large Midwestern pediatric academic medical center. The objectives were to evaluate recruitment success of ongoing trials and ascertain contributors to differential recruitment rates. We hypothesized that studies with good recruitment of eligible subjects would share characteristics not present in studies with lower than anticipated recruitment. The goal was to better understand barriers to good recruitment in pharmacogenetic studies to help inform future trial and infrastructure design. METHODS: Investigators designed a survey with proposed elements of success, which was then completed by lead and/or site investigators of all pharmacogenetics studies at the institution. Results were evaluated using an investigator-developed likelihood of success scoring system. RESULTS: Two studies recruited >95% of the approached eligible patients; 4 studies were consistent with investigator-anticipated recruitment (>50%), and 1 study did not meet expected recruitment. A study's total score on the investigator-devised scoring tool correlated well with the proportion of approached patients recruited (Pearson's correlation, r = 0.82; P < 0.001). Multiple factors impacted successful recruitment into these pharmacogenetic studies. Features of studies with successful recruitment included standardized clinical care, an ongoing team-patient relationship, severe and/or life-threatening outcome measures, study coordinator with experience in clinical research, a study medication with few or no alternative treatment options, and active involvement of the research team in clinical care. CONCLUSIONS: A scoring system for study characteristics may be useful to calculate the risk of failure for successful recruitment, allow discrimination among characteristics contributing to the risk, and permit study design alterations to improve likelihood of successful recruitment in pediatric pharmacogenetic studies.

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.

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.