Predictors of valproic acid steady-state serum levels in adult and pediatric psychiatric inpatients: a comparative analysis.

RATIONALE: Valproic acid (VPA) is commonly used as a second-line mood stabilizer or augmentative agent in severe mental illnesses. However, population pharmacokinetic studies specific to psychiatric populations are limited, and clinical predictors for the precision application of VPA remain undefined. OBJECTIVES: To identify steady-state serum VPA level predictors in pediatric/adolescent and adult psychiatric inpatients. METHODS: We analyzed data from 634 patients and 1,068 steady-state therapeutic drug monitoring (TDM) data points recorded from 2015 to 2021. Steady-state VPA levels were obtained after tapering during each hospitalization episode. Electronic patient records were screened for routine clinical parameters and co-medication. Generalized additive mixed models were employed to identify independent predictors. RESULTS: Most TDM episodes involved patients with psychotic disorders, including schizophrenia (29.2%) and schizoaffective disorder (17.3%). Polypharmacy was common, with the most frequent combinations being VPA + quetiapine and VPA + promethazine. Age was significantly associated with VPA levels, with pediatric/adolescent patients (< 18 years) demonstrating higher dose-adjusted serum levels of VPA (ß = 7.6±2.34, p < 0.001) after accounting for BMI. Women tended to have higher adjusted VPA serum levels than men (ß = 5.08±1.62, p < 0.001). The formulation of VPA (Immediate-release vs. extended-release) showed no association with VPA levels. Co-administration of diazepam exhibited a dose-dependent decrease in VPA levels (F = 15.7, p < 0.001), suggesting a potential pharmacokinetic interaction. CONCLUSIONS: This study highlights the utility of population-specific pharmacokinetic data for VPA in psychiatric populations. Age, gender, and co-administration of diazepam were identified as predictors of VPA levels. Further research is warranted to establish additional predictors and optimize the precision application of VPA in psychiatric patients.

Callous-Unemotional Traits and Face-Emotion Recognition as Mediators in Conduct Problems of Children With ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with increased risk for conduct problems (CP), as well as with callous-unemotional traits (CUt) and lower accuracy in face emotional recognition (FER). It is unclear, however, whether CUt and low accuracy in FER contribute to the risk for CP in ADHD. The present study investigated the possibility of such contribution. METHODS: This pilot study's participants included 31 children aged 7-17 years, diagnosed with ADHD, and treated in a psychiatric outpatient clinic. The parents rated their children on the ADHD Rating Scale, Inventory of Callous-Unemotional Traits, and the Child Behavior Checklist-Conduct Problems scale. Participants completed the Hebrew version of the children's Reading the Mind in the Eyes Test (cRMET)-a Theory of Mind measure. A bootstrapped multiple mediator model was used, adjusting for age and gender. RESULTS: ADHD symptoms were associated with CP. This association was not mediated by CUt or cRMET. CUt was associated with CP independent of ADHD symptom severity. CONCLUSIONS: ADHD symptoms and CUt both should be considered when assessing risk for CP and devising a treatment plan, in children with ADHD. Current results did not confirm the hypothesis that cRMET and CUt mediate between ADHD symptoms and CP. More studies employing larger samples, longitudinal design, and other emotion recognition measures are needed.

Body mass index increase in preschoolers with heterogeneous psychiatric diagnoses treated with risperidone.

OBJECTIVE: Use of risperidone in preschool-aged children is growing, with rising concerns of adverse metabolic consequences. Longitudinal data on risperidone-related weight gain in preschoolers are scarce. We aimed to evaluate changes in body mass index (BMI) that are associated with risperidone treatment in preschoolers. METHOD: We analyzed naturalistic, longitudinal data on 141 preschool children (112 boys, 29 girls) receiving psychiatric care. Mean patient age at baseline was 5.0 years (SD=0.8) and average follow-up period was 1.3 years (SD=0.8), with >8 mean BMI measurements per patient. We studied the effect of risperidone exposure (n=78) on age-and-sex-standardized BMI (BMI Z-score) implementing mixed models with random subject intercepts to account for repeated measures, covarying for multiple confounders including demographics, stimulant treatment and psychiatric diagnoses. We employed similar models to study dose and duration effects. RESULTS: Risperidone treatment was significantly associated with an increase in BMI (effect size of exposure=0.45 SD (SE=0.06), t (949)=7.7, p<0.001) covarying for stimulant exposure and other confounders, independent of treatment indication. Females exhibited stronger effects (risperidone treatment × sex interaction t=2.32, p=0.02)). Risperidone daily dose was associated with increase in BMI (for each additional 1 mg, effect size=0.28 SD (SE=0.07), t(419)=3.76, p<0.001). CONCLUSION: Similar to older populations, risperidone treatment in preschoolers is associated with significant weight gain, with evidence for dose effects. Findings provide critical data that can inform clinicians.

The Placebo Response in Adult ADHD as Objectively Assessed by the TOVA Continuous Performance Test.

Objective: We compared the placebo response (PR) as measured by the Test of Variables of Attention (TOVA) and the Conners' Adult ADHD Rating Scale (CAARS) scores. Method: A retrospective data analysis from a double-blind placebo-controlled study of metadoxine-ER in adults with ADHD. An additional database was used for comparison to TOVA response after methylphenidate challenge (TOVA-MPH-R). Results: PR was highest when calculated from the TOVA-Attention Composite Score (ACS). The PR showed significantly fewer variables improving concomitantly compared with MPH-R. The most prominent correlation between the CAARS-PR and the TOVA-PR was in the Omissions score (p = .032), which was age-dependent (b = .0007, p <.001). Discussion: TOVA-PR has an index-specific profile compared with CAARS-PR and TOVA-MPH-R. The partial correlation of TOVA-PR with CAARS-PR suggests that a composite score of TOVA specific indices and CAARS could have a synergic impact to improve the reliability of the response assessment in adult ADHD.

Characterizing the Placebo Response in Adults With ADHD.

Objective: Several ADHD pharmacological trials reported high placebo response (PR) rates. This study aims to characterize the PR in adult ADHD. Method: A retrospective cohort analysis of the placebo arm (140 adults with ADHD, 18-55 yrs, M:F 46.4%-53.6%) of a 6-week randomized, multicenter, double-blind metadoxine study, using Conners' Adult ADHD Rating Scale (CAARS) and the Adult ADHD Self-Report Scale (ASRS), was conducted. Results: Pre-post changes in placebo-treated adults were significant for both the CAARS and ASRS, F(2.9, 404.5) = 61.2, p < .00001, F(2.8, 383.0) = 43.1, p < .00001, respectively. Less than half of the participants had a PR which began early in treatment and persisted; almost 50% had a variable, inconsistent PR. Conclusion: In the current sample, PR in adult ADHD was prominent on both symptom scales and the investigator-rater instrument. Therefore, using investigator ratings as a primary endpoint does not necessarily attenuate PR. Of note, about half of the PR is variable, suggesting unreliable determination of efficacy.

Continuous Performance Test Is Sensitive to a Single Methylphenidate Challenge in Preschool Children With ADHD.

Objective: There is a lack of evidence-based diagnostic paradigms and personalized interventions for preschoolers with ADHD. This study aimed to evaluate the performance of preschoolers diagnosed with ADHD on a continuous performance test (CPT) before and after a single methylphenidate (MPH) challenge. Method: The Test of Variables of Attention (TOVA)-a CPT-was administered to 61 preschoolers (5.64 ± 0.69 years; 74% boys) with ADHD before and after a single MPH challenge (0.3 or 0.5 mg/kg). Baseline TOVA performance was correlated with Conners' Rating Scales (CRS) and compared with post-MPH TOVA performance. Results: A high rate of omission errors and several significant correlations between TOVA values and CRS scores were found at baseline. A single MPH administration improved TOVA performance significantly and was well tolerated. Conclusion: TOVA assessment may assist in the evaluation of the effect of MPH in preschoolers with ADHD and may help in planning interventions for them.

Demographic and Clinical Predictors of Hospitalization in Preschoolers With ADHD.

Objective: This chart review study characterized demographic and clinical indicators of the need for hospitalization in preschoolers with ADHD. Method: Medical records of preschoolers with Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR) ADHD during 2009-2012 were systematically reviewed. The cohort included 111 children (aged 5.13 ± 0.55 years, 77.47% boys). The demographic and clinical variables of hospitalized at a day-care unit (n = 30) and nonhospitalized (n = 81) preschoolers were compared. Results: Hospitalized preschoolers were younger (p < .0001), had higher rates of unmarried mothers (p < .001), and a higher number of comorbidities. The number of inattentive/hyperactivity-impulsivity symptoms was similar in both groups. Neurodevelopmental comorbidity (p < .0001), but not externalized (p = .82) or internalized (p = .20) psychopathology, was significantly higher in the hospitalized group. Conclusion: ADHD severity in preschoolers tends to be associated with younger age, specific parenthood constellations, and a high rate of neurodevelopmental, but not other, comorbidities. These findings emphasize the importance of the neurodevelopmental context in planning ADHD interventions at preschool age.

Effectiveness of parental training, methylphenidate treatment, and their combination on academic achievements and behavior at school of children with attention-deficit hyperactivity disorder.

This study aimed to compare the effectiveness of parental training (PT), methylphenidate treatment (MPH), and the combination of PT and MPH treatment (PT/MPH) on school achievements in children with attention-deficit hyperactivity disorder (ADHD). Twenty eight ADHD patients (age: 10.1±1.11 years) were divided into three groups: (a) PT (N=10), (b) PT/MPH (N=8), and (c) MPH alone (N=10). Their grades in academics and conduct, from their school reports before and after treatment (6 months), were coded as achievement scores. No significant differences in baseline academic and conduct scores were found between the groups (F=0.033, d.f.=2, P=0.97 and F=0.024, d.f.=2, P=0.98, respectively). No significant changes before versus after treatment were detected in academic (3.83±0.93 vs. 3.85±0.88, paired t=0.086, d.f.=9, P=0.93, NS) or conduct (3.90±1.10 vs. 4.10±1.00, paired t=1.50, d.f.=9, P=0.17, NS) scores in the PT group. The same was true for the PT/MPH group (academic scores: 3.75±0.98 vs. 4.05±0.83, d.f.=7, t=0.927, P=0.38; conduct scores: 3.85±0.83 vs. 4.12±0.83, d.f.=7, t=0.79, P=0.45). Only the MPH group showed significant improvements in those scores (academic scores: 3/73±0.85 vs. 4/44±0.48, d.f.=9, t=3.33, P=0.0088; conduct scores: 3.80±0.70 vs. 4.60±0.70, d.f.=9, t=3.2, P=0.011). Methylphenidate alone is superior to either parental training or parental training/methylphenidate in improving academics and conduct at school.

The reliability, concurrent validity and association with salivary oxytocin of the self-report version of the Inventory of Callous-Unemotional Traits in adolescents with conduct disorder.

The present study evaluated the self-report version of the Inventory of Callous-Unemotional Traits (ICU-SR) in terms of reliability, concurrent validity, and correlation with salivary oxytocin levels, a potential biomarker of CU traits. 67 socially at-risk male adolescents (mean 16.2 years) completed the ICU-SR, ICU teacher-version (ICU-TR), Strengths and Difficulties Questionnaire, and their medical files were coded for previous antisocial acts using Brown-Goodwin Lifetime Aggression Scale. Salivary samples were assayed for oxytocin. The reliability of ICU-SR was lower (α = 0.71) than ICU-TR (α = 0.86). ICU-SR mean score was significantly lower than ICU-TR (M = 25.29, SD = 8.02; M = 33.14, SD = 9.47). ICU-TR but not ICU-SR, significantly correlated with history of antisocial acts (r = 0.40). Two-way analysis of variance showed a significant effect of conduct disorder and oxytocin on ICU-TR but not ICU-SR [F(1,59) = 6.53; F(1,59) = 6.08], and a significant interaction only for ICU-TR [F(1,59) = 2.89]. Subjective self-reports of CU traits may be less reliable and valid than teachers' reports.

The Outcome of Severe Internalizing and Disruptive Disorders from Preschool into Adolescence:A Follow-up Study.

PURPOSE: In this study we aimed to examine the outcome of children's severe psychiatric disorders from preschool into later childhood and adolescence. METHOD: Forty preschool children (28 boys and 12 girls) treated in a tertiary referral mental health center, evaluated at admission and 5.5 ± 1.2 years thereafter. RESULTS: Seven (58.3%) children diagnosed with internalizing disorders at baseline were free of any psychiatric diagnosis at follow-up (p=0.02). Conversely, only one child (8.3%) diagnosed with comorbid disruptive-internalizing disorders at baseline was free of any psychiatric disorder at follow-up (p=1.0). Seven (43.7%) children diagnosed with disruptive disorders at baseline were free of psychiatric diagnoses at follow-up (p=0.02). LIMITATIONS: The small sample size and naturalistic nature of the study. CONCLUSION: The trajectories of severe psychiatric disorders at preschool years are similar to those reported in community samples and differ according to the baseline diagnosis. Children with internalizing disorders show a much better recovery rate than those with comorbid disruptive and internalizing disorders.

[Nosology, assessment and diagnosis of psychiatric disorders in early childhood].

The first 5 years of life, the period called "early childhood", are characterized by a dynamic process of development and maturation of the central nervous system (CNS). This process is manifested by continuous changes in cognitive, motor, speech/language, psychological and sensory modulation skills and consequently, in the behavior of the developing child. It is a period of neuron-plasticity, in which the CNS structure and functioning are very sensitive to environmental influences. These influences could be positive or negative. On the one hand, early protective factors, like secure attachment, increase the resilience of the very young child against stressors and against the development of psychopathology; but on the other hand, there is a high vulnerability to early insults of any kind. It has been demonstrated that a high percentage of psychopathology in adult life has his roots in early childhood, and that early diagnosis, which leads to early therapeutic interventions, decreases morbidity and the later life consequences of the disorders. These findings have promoted the field of early childhood psychiatry during the last decade, to become one of the most promising challenges in the field of mental health. In our review, we present an update on the state of nosology, assessment and diagnosis in early childhood and provide clinical guidelines for the daily work of professionals involved in the mental health care of very young children.