Risperidone plasma concentrations are associated with side effects and effectiveness in children and adolescents with autism spectrum disorder.

AIM: Risperidone is the most commonly prescribed antipsychotic drug to children and adolescents worldwide, but it is associated with serious side effects, including weight gain. This study assessed the relationship of risperidone and 9-hydroxyrisperidone trough concentrations, maximum concentrations and 24-hour area under the curves (AUCs) with body mass index (BMI) z-scores in children and adolescents with autism spectrum disorder (ASD) and behavioural problems. Secondary outcomes were metabolic, endocrine, extrapyramidal and cardiac side effects and effectiveness. METHODS: Forty-two children and adolescents (32 males) aged 6-18 years were included in a 24-week prospective observational trial. Drug plasma concentrations, side effects and effectiveness were measured at several time points during follow-up. Relevant pharmacokinetic covariates, including medication adherence and CYP2D6, CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) genotypes, were measured. Nonlinear mixed-effects modelling (NONMEM®) was used for a population pharmacokinetic analysis with 205 risperidone and 205 9-hydroxyrisperidone concentrations. Subsequently, model-based trough concentrations, maximum concentrations and 24-hour AUCs were analysed to predict outcomes using generalized and linear mixed-effects models. RESULTS: A risperidone two-compartment model combined with a 9-hydroxyrisperidone one-compartment model best described the measured concentrations. Of all the pharmacokinetic parameters, higher risperidone sum trough concentrations best predicted higher BMI z-scores during follow-up (P < .001). Higher sum trough concentrations also predicted more sedation (P < .05), higher prolactin levels (P < .001) and more effectiveness measured with Aberrant Behavior Checklist irritability score (P < .01). CONCLUSION: Our results indicate a therapeutic window exists, which suggests that therapeutic drug monitoring of risperidone might increase safety and effectiveness in children and adolescents with ASD and behavioural problems.

Risk factors and pattern of weight gain in youths using antipsychotic drugs.

Antipsychotic-induced weight gain is a major health concern in children and adolescents. The aim of this study was to identify risk factors for weight gain during short-, middle- and long-term treatment with antipsychotic drugs in this young population. We analysed a combined prospective and a retrospective observational cohort of Dutch children and adolescents, starting with risperidone, aripiprazole or pipamperone treatment. Linear mixed models were used to test whether sex, age, baseline body-mass-index (BMI) z score, type of antipsychotic, dose equivalent/kg, duration of use, previous antipsychotic use, ethnicity, physical exercise, IQ, concomitant medication, and psychiatric classification predicted the BMI z score for a follow-up of < 15 weeks, 15-52 weeks or > 52 weeks. A total of 144 patients were included with a median [interquartile range ([IQR)] age of 9 (4) years and median follow-up of 30 (73) weeks. During the complete follow-up, the median (IQR) weight gain was 0.37 (0.95) BMI z score points. Antipsychotic-induced weight gain was found to be most pronounced during the first 15 weeks of use (BMI z score increase per week ß = 0.02, 95% CI 0.01-0.03, p = 0.002). A higher baseline BMI z score and the absence of stimulant use were associated with a higher BMI z score during the entire follow-up and after 15 weeks, respectively. Previous treatment with an antipsychotic drug was associated with less weight gain during the first 15 weeks of treatment. Our findings underscore the importance of close patient monitoring during the first weeks of antipsychotic treatment with a focus on patients with a high baseline BMI z score.

Childbirth related PTSD and its association with infant outcome: A systematic review.

INTRODUCTION: Maternal postnatal mental health problems may negatively impact child development. Postpartum research has mainly focused on the impact of maternal depression and anxiety due to their high prevalence (13-25 % and 10-18 %, respectively). However, maternal childbirth-related PTSD (CB-PTSD) could be another important risk factor in child development (estimated prevalence: 4.7 %). OBJECTIVE: We investigated whether maternal CB-PTSD (symptoms) are associated with a negative mother-child relationship and/or child developmental outcome for children aged 0-5 years. Furthermore, we examined whether maternal trauma-focused therapy can positively impact mother and child outcomes. METHODS: We performed a systematic review by searching three databases (Embase, Medline, PsycInfo). Search terms involved: 'birth or delivery modes', 'PTSD psychological trauma', and 'child development or child behavior'. Two independent reviewers evaluated all eligible papers. RESULTS: Thirty-five papers (30 samples) were included and qualitatively reported. Results suggest a negative association of maternal CB-PTSD (symptoms) with mother-infant attachment and child behavior. However, confounding factors may explain this association. The evidence on associations with breastfeeding, sleeping, socio-emotional development, and weight gain is insufficient. Research investigating the effect of maternal trauma-focused therapy on a child's outcome is scarce, contradictory, and of low quality. CONCLUSION: This systematic review suggests that maternal CB-PTSD may be associated with an increased number of problems in mother-infant attachment and child behavior, but other domains remain scarcely investigated and methodologic issues are present (cross-sectional study design, influence of confounding variables, sample representativeness, diversity in assessment tools). Our results support a multidisciplinary approach to providing early prevention and screening of the maternal mental health state.

Should we use criteria or eyeballing to reject post-interruption tracings?

During the analysis of interrupter resistance (R(int))-measurements, most authors reject post-interruption tracings based on the shape of the pressure-time and flow-time curves. However, objective criteria for rejection are lacking. We aimed to formulate explicit rejection criteria that correspond to eyeballing the curve pattern (daily practice), in order to simplify the analysis. Inter-observer agreement within and between both methods was studied. Results obtained with the developed rejection criteria were compared to those of current practice (eyeballing) using 54 measurements (807 interruptions) of children with severe neurological impairment. Inter-observer agreement on rejection was similar using the criteria or eyeballing (85.6% vs. 82.8%). Using the criteria, more individual interruptions were rejected (43.4% vs. 29.8% using eyeballing), while discarding total measurements (<5 remaining interruptions) was similar (9.2% vs. 7.4% using eyeballing). Results using only the criteria for pressure-time curves were comparable to eyeballing. Outcome values were comparable between any of the used rejection methods and not rejecting at all. In this first detailed study on rejection of post-interruption tracings, explicit rejection criteria were developed. None of the rejection methods influenced the outcome value relevantly. However, rejection criteria can contribute to the standardization of the R(int) technique and simplify decision-making in daily practice.

Measuring body composition and energy expenditure in children with severe neurologic impairment and intellectual disability.

BACKGROUND: Accurate prediction equations for estimating body composition and total energy expenditure (TEE) in children with severe neurologic impairment and intellectual disability are currently lacking. OBJECTIVE: The objective was to develop group-specific equations to predict body composition by using skinfold-thickness measurements and bioelectrical impedance analysis (BIA) and to predict TEE by using data on mobility, epilepsy, and muscle tone. DESIGN: Measures of body composition with the use of skinfold-thickness measurements (percentage of body fat) and BIA (total body water) were compared with those from isotope dilution (reference method) by using intraclass correlation coefficients (ICCs) and Bland and Altman limits of agreement analyses. With the use of the same methods, the outcomes of cerebral palsy-specific TEE equations were compared with those of the doubly labeled water method (reference method). Group-specific regression equations were developed by using forward-stepwise-multiple-correlation-regression analyses. RESULTS: Sixty-one children with a mean (±SD) age of 10.1 ± 4.3 y (32 boys) were studied. A new equation based on the sum of 4 skinfold-thickness measurements did not improve agreement (n = 49; ICC = 0.61), whereas the newly developed BIA equation-which includes tibia length as an alternative for standing height-did improve agreement (n = 61; ICC = 0.96, SEE = 1.7 kg, R(2) = 0.92). The newly developed TEE equation, which uses body composition, performed better (n = 52; ICC = 0.87, SEE = 180 kcal, R(2) = 0.77) than did the equation of Schofield (n = 52; ICC = 0.82, SEE = 207 kcal, R(2) = 0.69). CONCLUSIONS: Current cerebral palsy-specific equations for measuring body composition and energy expenditure are inaccurate. BIA is more accurate at assessing nutritional status in this population than is the measurement of skinfold thickness. The newly developed TEE equation, which uses body composition, provides a reasonable estimate of energy expenditure in these children despite its variability.

Validation of skinfold measurements and bioelectrical impedance analysis in children with severe cerebral palsy: a review.

BACKGROUND & AIMS: Accurately measuring nutritional status in children with severe cerebral palsy (CP) is a challenge. This review seeks to assess the validity of skinfold measurements and bioelectrical impedance analysis (BIA) for measuring body composition in children with severe CP. METHODS: We executed a literature search on the validation of both methods in children with severe CP. To be eligible for inclusion, a study had to report on a statistical comparison between these two methods and any method of reference. The QUADAS tool was used for quality assessment. RESULTS: The search strategy resulted in 1549 studies of which 5 studies eventually met the inclusion criteria. When comparing body composition outcomes of skinfold measurements to a reference method, correlation coefficients were found ranging from 0.406 to 0.988. Correlation coefficients between body composition data of BIA and a reference method ranged from 0.515 to 0.95. CONCLUSIONS: Although a number of authors found favorable agreement between skinfold measurements and BIA in comparison with reference methods, the small numbers studied, the lack of methodological quality measured by QUADAS, and the use of inappropriate analytical methods hamper solid conclusions.

Energy intake does not correlate with nutritional state in children with severe generalized cerebral palsy and intellectual disability.

BACKGROUND & AIMS: The majority of children with cerebral palsy and intellectual disability has a poor nutritional state compared with their healthy peers. Several studies have found reduced daily energy intake in this population. The hypothesis is tested that low daily energy intake correlates with poor nutritional state. METHODS: In a population-based sample of 176 children with severe generalized cerebral palsy and intellectual disability (mean age 10 years, SD 2 months; 16% GMFCS score 4; 84% GMFCS score 5) anthropometric parameters (weight, upper arm and tibia length, biceps, triceps, subscapular and suprailiacal skinfold thickness, mid upper arm circumference) were measured and dietary intake was registered. RESULTS: No correlation was found between energy intake(%EAR) and anthropometric Z-scores. Higher age, female gender, mobility, and to a lesser extent the absence of tube feeding predicted lower anthropometric Z-scores. CONCLUSIONS: In children with severe generalized cerebral palsy and intellectual disability nutritional state is not primarily determined by energy intake. Differences in energy expenditure presumably play an important role, although more research is needed to clarify the complex association between energy intake and nutritional state. Individualized nutritional care is suggested, preferably based on energy expenditure, in order to avoid malnutrition, but also overweight.