Therapeutic Drug Monitoring in Children and Adolescents: Findings on Fluoxetine from the TDM-VIGIL Trial.

Fluoxetine is the recommended first-line antidepressant in many therapeutic guidelines for children and adolescents. However, little is known about the relationships between drug dose and serum level as well as the therapeutic serum reference range in this age group. Within a large naturalistic observational prospective multicenter clinical trial ("TDM-VIGIL"), a transdiagnostic sample of children and adolescents (n = 138; mean age, 15; range, 7-18 years; 24.6% males) was treated with fluoxetine (10-40 mg/day). Analyses of both the last timepoint and all timepoints (n = 292 observations), utilizing (multiple) linear regressions, linear mixed-effect models, and cumulative link (mixed) models, were used to test the associations between dose, serum concentration, outcome, and potential predictors. The receiver operating curve and first to third interquartile methods, respectively, were used to examine concentration cutoff and reference values for responders. A strong positive relationship was found between dose and serum concentration of fluoxetine and its metabolite. Higher body weight was associated with lower serum concentrations, and female sex was associated with lower therapeutic response. The preliminary reference ranges for the active moiety (fluoxetine+norfluoxetine) were 208-328 ng/mL (transdiagnostically) and 201.5-306 ng/mL (depression). Most patients showed marked (45.6%) or minimal (43.5%) improvements and reported no adverse effects (64.9%). This study demonstrated a clear linear dose-serum level relationship for fluoxetine in youth, with the identified reference range being within that established for adults.

Therapeutic drug monitoring of sertraline in children and adolescents: A naturalistic study with insights into the clinical response and treatment of obsessive-compulsive disorder.

BACKGROUND: Sertraline is a selective serotonin reuptake inhibitor with specific indications in child and adolescent psychiatry. Notwithstanding its frequent use and clinical benefits, the relationship between pharmacokinetics, pharmacodynamics, efficacy, and tolerability of sertraline across indications, particularly in non-adult patients, is not fully understood. METHOD: This naturalistic therapeutic drug monitoring (TDM) study was conducted in a transdiagnostic sample of children and adolescents treated with sertraline (n = 78; mean age, 14.22 ± 2.39; range, 7-18 years) within the prospective multicenter "TDM-VIGIL" project. Associations between dose, serum concentration, and medication-specific therapeutic and side effects based on the Clinical Global Impression scale were examined. Tolerability was measured qualitatively with the 56-item Pediatric Adverse Event Rating Scale. RESULTS: A strong linear positive dose-serum concentration relationship (with dose explaining 45% of the variance in concentration) and significant effects of weight and co-medication were found. Neither dose nor serum concentration were associated with side effects. An overall mild-to-moderate tolerability profile of sertraline was observed. In contrast with the transdiagnostic analysis that did not indicate an effect of concentration, when split into depression (MDD) and obsessive-compulsive disorder (OCD) diagnoses, the probability of clinical improvement significantly increased as both dose and concentration increased for OCD, but not for MDD. CONCLUSIONS: This TDM-flexible-dose study revealed a significant diagnosis-specific effect between sertraline serum concentration and clinical efficacy for pediatric OCD. While TDM already guides clinical decision-making regarding compliance, dose calibration, and drug-drug interactions, combining TDM with other methods, such as pharmacogenetics, may facilitate a personalized medicine approach in psychiatry.

Age dependency of body mass index distribution in childhood and adolescent inpatients with anorexia nervosa with a focus on DSM-5 and ICD-11 weight criteria and severity specifiers.

Both DSM-5 and ICD-11 have provided weight cut-offs and severity specifiers for the diagnosis of anorexia nervosa (AN) in childhood, adolescence and adulthood. The aims of the current study focusing on inpatients aged < 19 years were to assess (1) the relationship between age and body mass index (BMI; kg/m2), BMI-centiles, BMI-standard deviation scores (BMI-SDS) and body height-SDS at referral, (2) the percentages of patients fulfilling the DSM-5 and ICD-11 weight criteria and severity categories for AN, and (3) the validity of the AN severity specifiers via analysis of both weight related data at discharge and inpatient treatment duration. The German Registry for Anorexia Nervosa encompassed complete data sets for 469 female patients (mean age = 15.2 years; range 8.9-18.9 years) with a diagnosis of AN (n = 404) or atypical AN (n = 65), who were ascertained at 16 German child and adolescent psychiatric hospitals. BMI at referral increased up to age 15 to subsequently plateau. Approximately one tenth of all patients with AN had a BMI above the fifth centile. The ICD-11 specifier based on a BMI-centile of 0.3 for childhood and adolescent AN entailed two equally sized groups of patients. Discharge data revealed limited validity of the specifiers. Height-SDS was not correlated with age thus stunting had no impact on our data. We corroborate the evidence to use the tenth instead of the fifth BMI-centile as the weight criterion in children and adolescents. Weight criteria should not entail major diagnostic shifts during the transition from adolescence to adulthood. The severity specifiers based on BMI or BMI-centiles do not seem to have substantial clinical validity.

Outcome of childhood anorexia nervosa-The results of a five- to ten-year follow-up study.

OBJECTIVE: Although admissions of children with anorexia nervosa (AN) are increasing, there remains a dearth of up-to-date knowledge of the course and outcome of early-onset AN. The aim of the present study was to investigate the outcomes of patients with AN onset before the age of 14. METHOD: Sixty-eight consecutive former patients who met the DSM-IV criteria for AN and who had been treated at one of three German university hospitals were asked to participate in a follow-up study. Body mass index, body height, outcome of the eating disorder (ED), psychiatric morbidity, and health related quality of life (HRQoL) were assessed through a personal examination after an average time span of 7.5 years (range: 4.5-11.5 years) after admission. RESULTS: One patient had died. Fifty-two subjects with a mean age of 12.5 (SD 1.0) years at admission and of 20.2 (SD 2.0) years at follow-up agreed to participate in the follow-up assessment, aggregating to 77.9% of the original sample. Approximately 41% of the participants had a good outcome, while 35% and 24% had intermediate and poor outcomes, respectively. Twenty-eight percent of the sample met the DSM-IV criteria for a current non-ED psychiatric disorder, and 64% met the criteria for a past non-ED psychiatric disorder. Mental HRQoL and ED-specific psychopathology was strongly associated with the outcome of AN. Average body height was below the normal range. A higher weight at admission was the only significant positive indicator of outcome. DISCUSSION: Childhood AN is a serious disorder with an unfavorable course in many patients and high rates of chronicity and psychiatric comorbidity in young adulthood. Early detection and intervention are urgently needed.

The relationship between premorbid body weight and weight at referral, at discharge and at 1-year follow-up in anorexia nervosa.

Body mass index (BMI) is one of the most important outcome predictors in patients with anorexia nervosa (AN). A low premorbid BMI percentile calculated by the patients recalled premorbid weight and the height at first admission has been found to predict the BMI at first inpatient admission. In this study, we sought to confirm this relationship. We additionally analyze the relationship between premorbid BMI percentile and BMI percentile at discharge from the first inpatient treatment and at 1-year follow-up or alternatively if applicable upon readmission within this time period. We included 161 female patients aged 11-18 years of the multisite ANDI-trial with a DSM-IV diagnosis of AN. We used a multivariate statistical model including the independent variables age, duration of illness, duration of treatment, BMI at admission and BMI percentile at discharge. The relationship between premorbid BMI percentile and BMI at admission was solidly confirmed. In addition to premorbid BMI percentile, BMI at admission and age were significant predictors of BMI percentile at discharge. BMI percentile at discharge significantly predicted BMI percentile at 1-year follow-up. An additional analysis that merely included variables available upon referral revealed that premorbid BMI percentile predicts the 1-year follow-up BMI percentile. Further studies are required to identify the underlying biological mechanisms and to address the respective treatment strategies for AN patients with a low or high premorbid BMI percentile.