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.
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.
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.
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.
•The dose-, concentration- and age-related effects of SSRIs are not well understood.•The study was conducted in patients aged 7–18 treated with sertraline (25–250 mg/day).•Dose explained 45% of the variance in serum drug concentration across indications.•Clinical improvement was associated with dose and concentration in OCD, but not MDD.•Therapeutic drug monitoring is a promising tool in OCD research and therapy.
We aimed to compare the clinical data at first presentation to inpatient treatment of children (<14 years) vs. adolescents (≥14 years) with anorexia nervosa (AN), focusing on duration of illness ...before hospital admission and body mass index (BMI) at admission and discharge, proven predictors of the outcomes of adolescent AN. Clinical data at first admission and at discharge in 289 inpatients with AN (children:
= 72; adolescents:
= 217) from a German multicenter, web-based registry for consecutively enrolled patients with childhood and adolescent AN were analyzed. Inclusion criteria were a maximum age of 18 years, first inpatient treatment due to AN, and a BMI <10th BMI percentile at admission. Compared to adolescents, children with AN had a shorter duration of illness before admission (median: 6.0 months vs. 8.0 months,
= 0.004) and higher BMI percentiles at admission (median: 0.7 vs. 0.2,
= 0.004) as well as at discharge (median: 19.3 vs. 15.1,
= 0.011). Thus, in our study, children with AN exhibited clinical characteristics that have been associated with better outcomes, including higher admission and discharge BMI percentile. Future studies should examine whether these factors are actually associated with positive long-term outcomes in children.
Body mass index (BMI) at hospital admission in patients with anorexia nervosa (AN) represents a prognostic marker for mortality, chronicity and future body weight. The current study focused on the ...associations between BMI standard deviation score (BMI-SDS) at admission and reasons for seeking inpatient treatment. Further interest was given to the relationship between premorbid weight and weight at admission, as well as the effect of both weight at referral and reasons for admission on treatment outcome.
Data ascertained in the German Register of Children and Adolescents with AN were analysed to assess the parental and patient overlap for 23 predefined reasons for admission, using factor analyses and regressions models.
Complete parent-patient data sets were available for 360 patients out of 769. The highest consensus rates between parents and patients were obtained for weight and eating behavior related reasons and hyperactivity. Based on factor analysis, four factors emerged. Premorbid BMI-SDS, age and 'low body weight' as stated by patients or parents explained almost 40% of the variance of the BMI-SDS at admission.
Results underscore the relevance of age and premorbid BMI for BMI at admission. Only single reasons for admission explained further variance, with 'low body weight' having the largest effect. Approximately 40% of the variance of BMI-SDS was explained. For the first time, the effect of premorbid BMI for BMI at admission was robustly demonstrated in a multicenter study. Of the variance in BMI-SDS at discharge, our model could explain 37%, with reasons for admission having a small effect. Further investigation of the reasons for admission would be worthwhile to improve treatment and prognosis.
Most psychotropic drugs used in the treatment of children and adolescents are applied "off label" with a direct risk of under- or overdosing and a delayed risk of long-term side effects. The ...selection of doses in paediatric psychiatric patients requires a consideration of pharmacokinetic parameters and the development of central nervous system, and warrants specific studies in children and adolescents. Because these are lacking for most of the psychotropic drugs applied in the Child and Adolescent and Psychiatry, therapeutic drug monitoring (TDM) is a valid tool to optimise pharmacotherapy and to enable to adjust the dosage of drugs according to the characteristics of the individual patient. Multi-centre TDM studies enable the identification of age- and development-dependent therapeutic ranges of blood concentrations and facilitate a highly qualified standardized documentation in the child and adolescent health care system. In addition, they will provide data for future research on psychopharmacological treatment in children and adolescents, as a baseline for example for clinically relevant interactions with various co-medications. Therefore, a German-Austrian-Swiss "Competence Network on Therapeutic Drug Monitoring in Child and Adolescent Psychiatry" was founded 1 introducing a comprehensive internet data base for the collection of demographic, safety and efficacy data as well as blood concentrations of psychotropic drugs in children and adolescents.
To determine the prevalence of antibodies to Epstein-Barr virus (EBV) in a large cohort of patients with early multiple sclerosis (MS).
Serum samples were collected from 901 patients with a ...clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) participating in the German National MS cohort, a prospective cohort of patients with early MS with stringent inclusion criteria. Epstein-Barr nuclear antigen (EBNA)-1 and viral capsid antigen (VCA) antibodies were measured in diluted sera by chemiluminescence immunoassays (CLIAs). Sera of EBNA-1 and VCA antibody-negative patients were retested undiluted by an EBV IgG immunoblot. For comparison, we retrospectively analysed the EBV seroprevalence across different age cohorts, ranging from 0 to >80 years, in a large hospital population (N=16 163) from Berlin/Northern Germany.
EBNA-1 antibodies were detected by CLIA in 839 of 901 patients with CIS/RRMS. Of the 62 patients without EBNA-1 antibodies, 45 had antibodies to VCA as detected by CLIA. In all of the remaining 17 patients, antibodies to EBV were detected by immunoblot. Altogether, 901 of 901 (100%) patients with CIS/RRMS were EBV-seropositive. EBV seropositivity increased with age in the hospital population but did not reach 100% in any of the investigated age cohorts.
The complete EBV seropositivity in this large cohort of patients with early MS strengthens the evidence for a role of EBV in MS. It also suggests that a negative EBV serology in patients with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.
Obesity reportedly increases the risk for developing multiple sclerosis (MS), but little is known about its association with disability accumulation.
This nationwide longitudinal cohort study ...included 1066 individuals with newly diagnosed MS from the German National MS cohort. Expanded Disability Status Scale (EDSS) scores, relapse rates, MRI findings and choice of immunotherapy were compared at baseline and at years 2, 4 and 6 between obese (body mass index, BMI ≥30 kg/m
) and non-obese (BMI <30 kg/m
) patients and correlated with individual BMI values.
Presence of obesity at disease onset was associated with higher disability at baseline and at 2, 4 and 6 years of follow-up (p<0.001). Median time to reach EDSS 3 was 0.99 years for patients with BMI ≥30 kg/m
and 1.46 years for non-obese patients. Risk to reach EDSS 3 over 6 years was significantly increased in patients with BMI ≥30 kg/m
compared with patients with BMI <30 kg/m
after adjustment for sex, age, smoking (HR 1.87; 95% CI 1.3 to 2.6; log-rank test p<0.001) and independent of disease-modifying therapies. Obesity was not significantly associated with higher relapse rates, increased number of contrast-enhancing MRI lesions or higher MRI T2 lesion burden over 6 years of follow-up.
Obesity in newly diagnosed patients with MS is associated with higher disease severity and poorer outcome. Obesity management could improve clinical outcome of MS.
IMPORTANCE: Reliable biomarkers associated with disability worsening in multiple sclerosis (MS) are still needed. OBJECTIVE: To determine a possible association of intrathecal IgG synthesis and early ...disability worsening as measured by Expanded Disability Status Scale (EDSS) scoring in patients with relapsing-remitting MS or clinically isolated syndrome. DESIGN, SETTING, AND PARTICIPANTS: Cerebrospinal fluid measurements and clinical data from the observational longitudinal German national multiple sclerosis cohort were analyzed. Patients were recruited between August 2010 and November 2015 from 18 centers. Data analysis was completed from August 2018 to December 2018. EXPOSURE: Patients were offered standard immunotherapies per national treatment guidelines. MAIN OUTCOMES AND MEASURES: A possible association between intrathecal IgG synthesis and risk of EDSS worsening 4 years after study inclusion was tested as the primary end point by multivariable binomial regression analysis. Kaplan-Meier analysis with a log-rank test was used to assess the association of intrathecal IgG synthesis with the time to EDSS worsening. Associations between intrathecal IgM or IgA synthesis and other cerebrospinal fluid parameters and EDSS worsening were analyzed as exploratory end points. Data collection began before the hypotheses were formulated. RESULTS: Of all 1376 patients in the German Competence Network of Multiple Sclerosis cohort, 703 patients were excluded owing to missing cerebrospinal fluid or EDSS data. Of the 673 included patients, 459 (68.2%) were women. The mean (SD) age at baseline was 34 (10) years. Intrathecal IgG synthesis was associated with a higher risk of EDSS worsening after 4 years (odds ratio, 2.02 95% CI, 1.15-3.58; P = .01), independent of the occurrence of relapses and disease-modifying therapy. Additionally, intrathecal IgG synthesis was associated with earlier EDSS worsening; 4 years after study entry, worsening occurred in 28.4% (95% CI, 22.7%-34.1%) and 18.1% (95% CI, 12.4%-23.9%) of patients with and without intrathecal IgG synthesis, respectively. No association of other routine cerebrospinal fluid parameters with EDSS worsening was found. CONCLUSIONS AND RELEVANCE: Patients with new diagnoses of relapsing-remitting multiple sclerosis or clinically isolated syndrome with intrathecal IgG synthesis had a higher risk of and shorter time to EDSS worsening across a 4-year period of follow-up. Intrathecal IgG synthesis is a potentially useful marker for disability worsening in patients with multiple sclerosis and may be useful for early treatment decisions.
Objective
For adolescents, DSM‐5 differentiates anorexia nervosa (AN) and atypical AN with the 5th BMI‐centile‐for‐age. We hypothesized that the diagnostic weight cut‐off yields (i) lower weight loss ...in atypical AN and (ii) discrepant premorbid BMI distributions between the two disorders. Prior studies demonstrate that premorbid BMI predicts admission BMI and weight loss in patients with AN. We explore these relationships in atypical AN.
Method
Based on admission BMI‐centile < or ≥5th, participants included 411 female adolescent inpatients with AN and 49 with atypical AN from our registry study. Regression analysis and t‐tests statistically addressed our hypotheses and exploratory correlation analyses compared interrelationships between weight loss, admission BMI, and premorbid BMI in both disorders.
Results
Weight loss in atypical AN was 5.6 kg lower than in AN upon adjustment for admission age, admission height, premorbid weight and duration of illness. Premorbid BMI‐standard deviation scores differed by almost one between both disorders. Premorbid BMI and weight loss were strongly correlated in both AN and atypical AN.
Discussion
Whereas the weight cut‐off induces discrepancies in premorbid weight and adjusted weight loss, AN and atypical AN overall share strong weight‐specific interrelationships that merit etiological consideration. Epidemiological and genetic associations between AN and low body weight may reflect a skewed premorbid BMI distribution. In combination with prior findings for similar psychological and medical characteristics in AN and atypical AN, our findings support a homogenous illness conceptualization. We propose that diagnostic subcategorization based on premorbid BMI, rather than admission BMI, may improve clinical validity.
Public significance
Because body weights of patients with AN must drop below the 5th BMI‐centile per DSM‐5, they will inherently require greater weight loss than their counterparts with atypical AN of the same sex, age, height and premorbid weight. Indeed, patients with atypical AN had a 5.6 kg lower weight loss after controlling for these variables. In comparison to the reference population, we found a lower and higher mean premorbid weight in patients with AN and atypical AN, respectively. Considering previous psychological and medical comparisons showing little differences between AN and atypical AN, we view a single disorder as the most parsimonious explanation. Etiological models need to particularly account for the strong relationship between weight loss and premorbid body weight.
Abstract
Introduction
Despite the growing evidence base for psychotropic drug
treatment in pediatric patients, knowledge about the benefit-risk ratio in
clinical practice remains limited. The ...‘Therapeutic Drug Monitoring
(TDM)-VIGIL’ study aimed to evaluate serious adverse drug reactions
(ADRs) in children and adolescents treated with antidepressants and/or
antipsychotics in approved (‘on-label’), and off-label use in
clinical practice.
Methods
Psychiatric pediatric patients aged 6-18 years treated with
antidepressants and/or antipsychotics either on-label or off-label were
prospectively followed between October 2014 and December 2018 within a
multicenter trial. Follow-up included standardized assessments of response,
serious ADRs and therapeutic drug monitoring.
Results
710 youth (age=14.6±2.2 years,
female=66.6%) were observed for 5.5 months on average;
76.3% received antidepressants, 47.5% antipsychotics, and
25.2% both. Altogether, 55.2% of the treatment episodes with
antidepressants and 80.7% with antipsychotics were off-label. Serious
ADRs occurred in 8.3% (95%CI=6.4–10.6%)
of patients, mainly being psychiatric adverse reactions (77.4%),
predominantly suicidal ideation and behavior. The risk of serious ADRs was not
significantly different between patients using psychotropics off-label and
on-label (antidepressants: 8.1% vs. 11.3%, p=0.16;
antipsychotics: 8.7% vs 7.5%, p=0.67). Serious ADRs
occurred in 16.6% of patients who were suicidal at enrollment versus
5.6% of patients who were not suicidal (relative risk 3.0,
95%CI=1.9-4.9).
Conclusion
Off-label use of antidepressants and antipsychotics in youth
was not a risk factor for the occurrence of serious ADRs in a closely monitored
clinical setting. Results from large naturalistic trials like ours can
contribute to bridging the gap between knowledge from randomized controlled
trials and real-world clinical settings.
Abstract The COVID-19 pandemic appears to have had a considerable impact on the mental health of children and adolescents, particularly regarding eating disorders. However, it remains unclear whether ...the pandemic affected only the frequency or also the severity of eating disorders. We examined potential pandemic-related changes in the administrative prevalence of eating disorders in the outpatient sector compared with other mental disorders using German statutory health insurance data for the age group 10 to 16 years. We also examined disorder severity of anorexia nervosa using data from the multicenter German Registry of Children and Adolescents with Anorexia Nervosa in the same age group. Our results showed a marked increase in the administrative prevalence of eating disorders (based on documented diagnoses) in the outpatient sector among girls but not among boys. A similar pattern was found for internalizing disorders, whereas the administrative prevalences of externalizing disorders decreased. Regarding the severity of anorexia nervosa among inpatients, we found no pandemic-related changes in body mass index standard deviation score at admission, body weight loss before admission, psychiatric comorbidities and psychopharmacological medication. Given the administrative prevalence increase in the outpatient sector, the lack of impact of the pandemic on the inpatient sector may also be partly due to a shift in healthcare utilization towards outpatient services during the pandemic. Thus, the higher number of children and adolescents requiring specialized and timely outpatient care may be a major concern under pandemic conditions.
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