Investigating thyroid function and iodine status in adolescents with and without paediatric major depressive disorder.

Depression has been associated with subclinical hypothyroidism and altered hypothalamic-pituitary-thyroid axis functioning. Adequate iodine nutrition is essential for healthy thyroid functioning. We therefore determined associations of iodine and thyroid status with paediatric major depressive disorder (pMDD) among Swiss adolescents and explored whether associations are sex-specific and mediated by stress. We conducted a matched case-control study in 95 adolescents with diagnosed pMDD and 95 healthy controls. We assessed depression severity using the Children's Depression Rating Scale-Revised and stress using the perceived stress scale (PSS) and measuring hair cortisol levels. We determined iodine status by measuring urinary iodine concentrations (UIC) and thyroid status by thyroid-stimulating hormone (TSH) and free thyroxine (FT4) in serum. Median (IQR) UIC did not differ between cases (121 (87, 174) µg/l) and controls (114 (66, 183) µg/l, P = 0·3). Median TSH and FT4 were lower in cases than controls (TSH: 1·36 (0·91, 2·00) mlU/l v. 1·50 (1·18, 2·06) mlU/l, P = 0·039; FT4: 14·7 (12·9, 16·9) pmol/l v. 15·7 (14·3, 17·2) pmol/l, P = 0·004). The prevalence of hypothyroxinaemia (normal TSH; low FT4) was higher among female cases than controls (21 % v. 4%, P = 0·006). PSS scores were higher while hair cortisol was lower in cases than controls (PSS: 25 (20, 28) v. 11 (7, 15), P < 0·001; cortisol: 2·50 (1·34, 3·57) pg/mg v. 3·23 (1·79, 4·43) pg/mg, P = 0·044). After adjusting for confounders, the associations of TSH and hair cortisol with pMDD were no longer significant. Furthermore, TSH and FT4 were not associated with PSS scores and hair cortisol levels. Summarising, iodine nutrition was adequate for adolescents with and without pMDD. However, FT4 concentrations were lower in those with pMDD, and 1 in 5 female adolescents with pMDD were hypothyroxinaemic.

Effectiveness of Omega-3 Fatty Acids Versus Placebo in Subjects at Ultra-High Risk for Psychosis: The PURPOSE Randomized Clinical Trial.

BACKGROUND AND HYPOTHESES: In the past 2 decades, substantial effort has been put into research on therapeutic options for people at ultra-high risk (UHR) for developing a first episode of psychosis (FEP), focusing on omega-3 polyunsaturated fatty acids (PUFAs) in preventing transition to psychosis. Despite an initial positive finding, subsequent studies failed to find a beneficial effect. The current study aimed to further investigate the effect of omega-3 PUFAs in UHR, to determine whether this line of research is worth pursuing. STUDY DESIGN: A double-blind, randomized, placebo-controlled study testing the efficacy of 6-month treatment with omega-3 PUFAs in 135 subjects at UHR for FEP, aged 13 to 20 years on the prevention of a transition to psychosis, followed up for 18 months post-treatment. The trial was conducted at 16 general hospitals and psychiatric specialty centers located in 8 European countries and Israel. STUDY RESULTS: There was no beneficial effect of treatment with omega-3 PUFAs compared to placebo; the rate of transition over 2 years did not differ between treatment arms nor was there a difference in change in symptom severity after 6-month treatment. Dropout rates and serious adverse events were similar across the groups. CONCLUSIONS: This is the third study that fails to replicate the original finding on the protective effect of omega-3 PUFAs in UHR subjects for transition to psychosis. The accumulating evidence therefore suggests that omega-3 PUFAs do not reduce transition rates to psychosis in those at increased risk at 2 years follow-up. CLINICAL TRIALS: This trial is registered with ClinicalTrials.gov (NCT02597439; Study Details | Placebo-controlled Trial in Subjects at Ultra-high Risk for Psychosis With Omega-3 Fatty Acids in Europe | ClinicalTrials.gov).

Generation of induced pluripotent stem cells from ADHD patients who do or do not respond to Methylphenidate treatment.

As a neurodevelopmental multifactorial disorder whose prevalence has been increasing worldwide, attention-deficit hyperactivity disorder (ADHD) is considered a public health concern. Methylphenidate (MPH) is the drug of choice for ADHD; however, not all patients respond fully to this treatment. Therefore, exploring the underlying molecular mechanisms involved in ADHD and potential novel therapeutic targets is crucial. Here, we generated induced pluripotent stem cells (iPSCs) from Peripheral Blood Mononuclear Cells (PBMCs) retrieved from four ADHD patients (two MPH responders and two non-responders) using Sendai virus. These lines might be helpful for the in vitro investigation of ADHD pathophysiology in a patient-specific manner.

Timing and cortical region matter: theta power differences between teenagers affected by Major Depression and healthy controls.

In adults affected by Major Depressive Disorder (MDD), most findings point to higher electroencephalographic (EEG) theta power during wake compared to healthy controls (HC) as a potential biomarker aiding the diagnostic process or subgrouping for stratified treatment. Besides these group differences, theta power is modulated by time of day, sleep/wake history, and age. Thus, we aimed at assessing if the time of recording alters theta power in teenagers affected by MDD or HC. Standardized wake EEG power was assessed with high-density EEG in 15 children and adolescents with MDD and in 15 age- and sex-matched HC in the evening and morning. Using a two-way ANOVA, group, time, and their interaction were tested. In patients, the current severity of depression was rated using the Children's Depression Rating Scale. Broadband EEG power was lower in the morning after sleep, with a significant interaction (group x time) in central regions in the 4-6 Hz range. In MDD relative to HC, theta power was decreased over occipital areas in the evening and increased over frontal areas in the morning. A higher frontal theta power was correlated with more severe depressive mood in the morning but not in the evening. This was a cross-sectional study design, including patients on antidepressant medication. In conclusion, depending on time of recording, region-specific opposite differences of theta power were found between teenagers with MDD and HC. These findings stress the importance of the time of the recording when investigating theta power's relationship to psychopathology.

Hypomania-Checklist-33: risk stratification and factor structure in a mixed psychiatric adolescent sample.

BACKGROUND: The 33-item Hypomania Checklist (HCL-33) has been shown to distinguish between adolescent bipolar disorder (BD) and unipolar depression. To investigate the utility of the HCL-33 as a screening tool in routine diagnostics, the frequency and psychopathological characteristics of detected individuals in a mixed psychiatric sample necessitate more examination. METHODS: The HCL-33, Children's Depression Inventory, Beck's Anxiety Inventory, and Strengths and Difficulties Questionnaire were completed by 285 children and adolescents (12-18 years) in a mixed psychiatric sample. Applying the proposed HCL-33 cut-off score of ≥ 18, individuals with depressive symptoms were divided into at-risk or not at-risk for BD groups. The factorial structure, sum and factor score correlations with psychopathology, and impact on daily functioning were assessed. RESULTS: 20.6% of the sample met at-risk criteria for BD. These individuals (n = 55) were older, more anxious, and showed more conduct problems vs the not at-risk group (n = 107). A two- and a three-factor model were pursued with the same Factor 1 ("active-elated"). Factor 2 ("risk-taking/irritable") was separated into 2a ("irritable-erratic") and 2b ("outgoing-disinhibited") in the three-factor model. Whereas higher Factor 2 and 2a scores correlated with a broad range of more severe symptomatology (i.e., depression, anxiety, hyperactivity), higher Factor 1 and 2b scores correlated with more emotional and conduct problems, respectively. 51.7% of the sample reported a negative impact from hypomanic symptoms on daily functioning. LIMITATIONS: Cross-sectional design and data collection in a single mental health service. CONCLUSIONS: The HCL-33 may be a useful tool to improve diagnostics, especially in adolescents with depressive symptoms additionally presenting with anxious symptoms and conduct problems.

Omega-3 alleviates behavioral and molecular changes in a mouse model of stress-induced juvenile depression.

Introduction: Depression is increasingly diagnosed in adolescence, necessitating specific prevention and treatment methods. However, there is a lack of animal models mimicking juvenile depression. This study explores a novel model using ultrasound (US) stress in juvenile mice. Methods: We employed the US stress model in one-month-old C57/BL6 mice, exposing them to alternating ultrasound frequencies (20-25 kHz and 25-45 kHz) for three weeks. These frequencies correspond to negative and neutral emotional states in rodents and can induce a depressive-like syndrome. Concurrently, mice received either an omega-3 food supplement (FS) containing eicosapentaenoic acid (EPA; 0.55 mg/kg/day) and docosahexaenoic acid (DHA; 0.55 mg/kg/day) or a vehicle. Post-stress, we evaluated anxiety- and depressive-like behaviors, blood corticosterone levels, brain expression of pro-inflammatory cytokines, and conducted metabolome analysis of brain, liver and blood plasma. Results: US-exposed mice treated with vehicle exhibited decreased sucrose preference, a sign of anhedonia, a key feature of depression, increased anxiety-like behavior, elevated corticosterone levels, and enhanced TNF and IL-1ß gene expression in the brain. In contrast, US-FS mice did not display these changes. Omega-3 supplementation also reduced anxiety-like behavior in non-stressed mice. Metabolomic analysis revealed US-induced changes in brain energy metabolism, with FS increasing brain sphingomyelin. Liver metabolism was affected by both US and FS, while plasma metabolome changes were exclusive to FS. Brain glucose levels correlated positively with activity in anxiety tests. Conclusion: Chronic omega-3 intake counteracted depressive- and anxiety-like behaviors in a US model of juvenile depression in mice. These effects likely stem from the anti-inflammatory properties of the supplement, suggesting potential therapeutic applications in juvenile depression.

Weakened effective connectivity between salience network and default mode network during resting state in adolescent depression.

Adolescent major depressive disorder (MDD) is associated with altered resting-state connectivity between the default mode network (DMN) and the salience network (SN), which are involved in self-referential processing and detecting and filtering salient stimuli, respectively. Using spectral dynamical causal modelling, we investigated the effective connectivity and input sensitivity between key nodes of these networks in 30 adolescents with MDD and 32 healthy controls while undergoing resting-state fMRI. We found that the DMN received weaker inhibition from the SN and that the medial prefrontal cortex and the anterior cingulate cortex showed reduced self-inhibition in MDD, making them more prone to external influences. Moreover, we found that selective serotonin reuptake inhibitor (SSRI) intake was associated with decreased and increased self-inhibition of the SN and DMN, respectively, in patients. Our findings suggest that adolescent MDD is characterized by a hierarchical imbalance between the DMN and the SN, which could affect the integration of emotional and self-related information. We propose that SSRIs may help restore network function by modulating excitatory/inhibitory balance in the DMN and the SN. Our study highlights the potential of prefrontal-amygdala interactions as a biomarker and a therapeutic target for adolescent depression.

Inverse association between slow-wave sleep and low-grade inflammation in children and adolescents with major depressive disorder.

OBJECTIVE: To investigate the relationship between both self-reported and objective sleep variables and low-grade inflammation in children and adolescents with major depressive disorder (MDD) of moderate to severe symptom severity. METHODS: In this cross-sectional study, we examined twenty-nine children and adolescents diagnosed with MDD and twenty-nine healthy controls (HC). Following a one-week actigraphy assessment, comprehensive sleep evaluations were conducted, including a one-night sleep EEG measurement and self-reported sleep data. Plasma high-sensitivity C-reactive protein (hsCRP) was employed as a marker to assess low-grade inflammation. RESULTS: No significant difference in hsCRP levels was observed between participants with MDD and HC. Furthermore, after adjusting for sleep difficulties, hsCRP exhibited no correlation with the severity of depressive symptoms. In HC, levels of hsCRP were not linked to self-reported and objective sleep variables. In contrast, depressed participants showed a significant correlation between hsCRP levels and increased subjective insomnia severity (Insomnia Severity Index; r = 0.41, p < 0.05), increased time spent in the N2 sleep stage (r = 0.47, p < 0.01), and decreased time spent in slow-wave sleep (r = - 0.61, p < 0.001). Upon additional adjustments for body mass index, tobacco use and depression severity, only the inverse association between hsCRP and time spent in slow-wave sleep retained statistical significance. Moderation analysis indicated that group status (MDD vs. HC) significantly moderates the association between slow-wave sleep and hsCRP. CONCLUSION: Our findings suggest that alterations in the architecture of slow-wave sleep may have a significant influence on modulating low-grade inflammatory processes in children and adolescents with MDD.

Randomized controlled trial of individualized arousal-biofeedback for children and adolescents with disruptive behavior disorders (DBD).

Disruptive behavior disorders [including conduct disorder (CD) and oppositional defiant disorder (ODD)] are common childhood and adolescent psychiatric conditions often linked to altered arousal. The recommended first-line treatment is multi-modal therapy and includes psychosocial and behavioral interventions. Their modest effect sizes along with clinically and biologically heterogeneous phenotypes emphasize the need for innovative personalized treatment targeting impaired functions such as arousal dysregulation. A total of 37 children aged 8-14 years diagnosed with ODD/CD were randomized to 20 sessions of individualized arousal biofeedback using skin conductance levels (SCL-BF) or active treatment as usual (TAU) including psychoeducation and cognitive-behavioral elements. The primary outcome was the change in parents´ ratings of aggressive behavior measured by the Modified Overt Aggression Scale. Secondary outcome measures were subscales from the Child Behavior Checklist, the Inventory of Callous-Unemotional traits, and the Reactive-Proactive Aggression Questionnaire. The SCL-BF treatment was neither superior nor inferior to the active TAU. Both groups showed reduced aggression after treatment with small effects for the primary outcome and large effects for some secondary outcomes. Importantly, successful learning of SCL self-regulation was related to reduced aggression at post-assessment. Individualized SCL-BF was not inferior to active TAU for any treatment outcome with improvements in aggression. Further, participants were on average able to self-regulate their SCL, and those who best learned self-regulation showed the highest clinical improvement, pointing to specificity of SCL-BF regulation for improving aggression. Further studies with larger samples and improved methods, for example by developing BF for mobile use in ecologically more valid settings are warranted.

Polygenic risk for Alzheimer's disease is associated with neuroaxonal damage before onset of clinical symptoms.

INTRODUCTION: Establishing valid diagnostic strategies is a precondition for successful therapeutic intervention in Alzheimer's disease (AD). METHODS: One hundred forty-four healthy 75-year-old participants from the Vienna-Transdanube-Aging longitudinal cohort study were tested for neuroaxonal damage by single molecular array (Simoa) plasma neurofilament light chain (NfL) levels at baseline, 30, 60, and 90 months, and onset of AD dementia. Individual risk for sporadic AD was estimated by continuous shrinkage polygenic risk score (PRS-CS, genome-wide association study). RESULTS: Nineteen participants developed AD after a median of 60 months (interquartile range 30). In participants with AD, baseline NfL plasma levels correlated with PRS-CS (r = 0.75, p < 0.001; difference to controls: Fisher's r-to-z: z = 3.89, p < 0.001). PRS-CS combined with baseline plasma NfL predicted onset of AD (p < 0.01). DISCUSSION: Our data suggest that polygenic risk for AD and plasma NfL closely interact years before onset of clinical symptoms. Peripheral NfL may serve as a diagnostic measure supporting early therapeutic intervention and secondary prevention in AD.

Stress as a mediator of brain alterations in attention-deficit hyperactivity disorder: A systematic review.

OBJECTIVE: Stress is a known risk factor for numerous psychopathologies, whereas evidence is lacking regarding the specific consequences of stress on the neural basis of attention-deficit hyperactivity disorder (ADHD). A systematic literature review was thus conducted to clarify the role of stress in the association between the resulting alterations of brain structure, connectivity, and function in ADHD. METHODS: The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under identifier CRD42023379809. A systematic search of the PubMed and CINAHL databases was conducted for articles published prior to December 22nd, 2022. Retrieved literature was screened in Rayyan and data extraction was performed with respect to neuroimaging, stress exposure, and ADHD outcomes. The Quality in Prognosis Studies (QUIPS) tool was adapted based on the Conducting Systematic Reviews and Meta-Analyses of Observational Studies of Etiology (COSMOS-E) guidance article to assess risk of bias and quality of studies. Strength of the evidence was assessed under the guidance of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. RESULTS: Screening 25,026 non-duplicate articles yielded 20 eligible studies for inclusion. Exposure to early life trauma, institutionalization, prenatal smoking or alcohol consumption, air pollution, low socioeconomic status, or low birth weight were associated with alterations in brain structure, function, and connectivity in ADHD. However, most studies did not provide strong evidence due to small sample sizes and lack of statistical approaches to determine a direct mediation of the association between stress and ADHD by neural outcomes. CONCLUSION: This systematic review was the first to summarize evidence of structural and functional stress-associated alterations in the brain, which were found to be directly and indirectly associated with ADHD outcomes. Overall, stress requires consideration as a significant determinant of neurodevelopmental outcomes in ADHD. However, extensive further research is warranted due to little available evidence and the difficulty of obtaining clear results. In light of such a complex research question, in order to confirm findings, provide further evidence, and establish causality systematic longitudinal studies would be required. Investigating the topic may provide invaluable information when it comes to tailoring prevention and treatment strategies in ADHD, and should be pursued in order to integrate the factor of stress into a more comprehensive understanding of ADHD.

Effects of including a dog on treatment motivation and the therapeutic alliance in child and adolescent psychotherapy: study protocol for a randomized controlled trial.

BACKGROUND: Motivation and a therapeutic alliance are crucial for successful therapy. It is assumed that dogs can increase motivation and help support therapeutic relationships. This is one of the reasons for including dogs in psychotherapy. While the positive effects of psychotherapy with dogs have been documented over the past years, little is known about the underlying mechanisms of animal-assisted psychotherapy. This study therefore aims to investigate whether and how the presence of a dog affects motivation and the therapeutic alliance in child and adolescent psychotherapy. METHODS: The study is a randomized controlled trial assessing motivation and the therapeutic alliance during the first five sessions of psychotherapy attended by children and adolescents with different psychiatric disorders. We will recruit 150 children and adolescents and randomly assign them to one of three conditions: (a) a dog is present but not integrated in the therapeutic narrative, (b) a dog is actively integrated in the therapeutic narrative, and (c) no dog is present. The children's and adolescents' evaluations of the therapeutic alliance and of their motivation will be assessed as the primary outcomes using standardized questionnaires before and after the first five therapy sessions as well as at follow-up. Further outcomes include the therapists' evaluations of the therapeutic alliance and their motivation, treatment adherence of the children and adolescents, and treatment satisfaction of the children and adolescents, their parents, and of the therapists. Interventions are conducted by experienced therapists who regularly work with their dogs. Outcomes will be analyzed using general linear models, with the treatment group as a fixed factor and the baseline values as covariates. DISCUSSION: This study provides information on the possible motivation and alliance-enhancing effects of integrating a dog into child and adolescent psychotherapy. This is relevant for practice, as these two components are strong predictors of therapy outcome. Moreover, the study will contribute to a better understanding of how a dog should be incorporated into psychotherapeutic settings. This can lead to a more purposeful inclusion of dogs in psychotherapy for children and adolescents. TRIAL REGISTRATION: The trial was registered on ClinicalTrials.gov, NCT05384808, on 20 May 2022.

Iron status in Swiss adolescents with paediatric major depressive disorder and healthy controls: a matched case-control study.

PURPOSE: Depression is associated with low-grade systemic inflammation and impaired intestinal function, both of which may reduce dietary iron absorption. Low iron status has been associated with depression in adults and adolescents. In Swiss adolescents, we determined the associations between paediatric major depressive disorder (pMDD), inflammation, intestinal permeability and iron status. METHODS: This is a matched case-control study in 95 adolescents with diagnosed pMDD and 95 healthy controls aged 13-17 years. We assessed depression severity using the Children's Depression Rating Scale-Revised. We measured iron status (serum ferritin (SF) and soluble transferrin receptor (sTfR)), inflammation (C-reactive protein (CRP) and alpha-1-acid-glycoprotein (AGP)), and intestinal permeability (intestinal fatty acid binding protein (I-FABP)). We assessed history of ID diagnosis and treatment with a self-reported questionnaire. RESULTS: SF concentrations did not differ between adolescents with pMDD (median (IQR) SF: 31.2 (20.2, 57.0) µg/L) and controls (32.5 (22.6, 48.3) µg/L, p = 0.4). sTfR was lower among cases than controls (4.50 (4.00, 5.50) mg/L vs 5.20 (4.75, 6.10) mg/L, p < 0.001). CRP, AGP and I-FABP were higher among cases than controls (CRP: 0.16 (0.03, 0.43) mg/L vs 0.04 (0.02, 0.30) mg/L, p = 0.003; AGP: 0.57 (0.44, 0.70) g/L vs 0.52 (0.41, 0.67) g/L, p = 0.024); I-FABP: 307 (17, 515) pg/mL vs 232 (163, 357) pg/mL, p = 0.047). Of cases, 44% reported having a history of ID diagnosis compared to 26% among controls (p = 0.020). Finally, 28% of cases had iron treatment at/close to study inclusion compared to 14% among controls. CONCLUSION: Cases had significantly higher systemic inflammation and intestinal permeability than controls but did not have lower iron status. Whether this is related to the higher rate of ID diagnosis and iron treatment in adolescents with depression is uncertain.

Psychopharmacology in children and adolescents: unmet needs and opportunities.

Psychopharmacological treatment is an important component of the multimodal intervention approach to treating mental health conditions in children and adolescents. Currently, there are many unmet needs but also opportunities, alongside possible risks to consider, regarding the pharmacological treatment of mental health conditions in children and adolescents. In this Position Paper, we highlight and address these unmet needs and opportunities, including the perspectives of clinicians and researchers from the European College of Neuropsychopharmacology-Child and Adolescent Network, alongside those of experts by lived experience from national and international associations, via a survey involving 644 participants from 13 countries, and of regulators, through representation from the European Medicines Agency. We present and discuss the evidence base for medications currently used for mental disorders in children and adolescents, medications in the pipeline, opportunities in the development of novel medications, crucial priorities for the conduct of future clinical studies, challenges and opportunities in terms of the regulatory and legislative framework, and innovations in the way research is conducted, reported, and promoted.

Different whole-brain functional connectivity correlates of reactive-proactive aggression and callous-unemotional traits in children and adolescents with disruptive behaviors.

BACKGROUND: Disruptive behavior in children and adolescents can manifest as reactive aggression and proactive aggression and is modulated by callous-unemotional traits and other comorbidities. Neural correlates of these aggression dimensions or subtypes and comorbid symptoms remain largely unknown. This multi-center study investigated the relationship between resting state functional connectivity (rsFC) and aggression subtypes considering comorbidities. METHODS: The large sample of children and adolescents aged 8-18 years (n = 207; mean age = 13.30±2.60 years, 150 males) included 118 cases with disruptive behavior (80 with Oppositional Defiant Disorder and/or Conduct Disorder) and 89 controls. Attention-deficit/hyperactivity disorder (ADHD) and anxiety symptom scores were analyzed as covariates when assessing group differences and dimensional aggression effects on hypothesis-free global and local voxel-to-voxel whole-brain rsFC based on functional magnetic resonance imaging at 3 Tesla. RESULTS: Compared to controls, the cases demonstrated altered rsFC in frontal areas, when anxiety but not ADHD symptoms were controlled for. For cases, reactive and proactive aggression scores were related to global and local rsFC in the central gyrus and precuneus, regions linked to aggression-related impairments. Callous-unemotional trait severity was correlated with ICC in the inferior and middle temporal regions implicated in empathy, emotion, and reward processing. Most observed aggression subtype-specific patterns could only be identified when ADHD and anxiety were controlled for. CONCLUSIONS: This study clarifies that hypothesis-free brain connectivity measures can disentangle distinct though overlapping dimensions of aggression in youths. Moreover, our results highlight the importance of considering comorbid symptoms to detect aggression-related rsFC alterations in youths.

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.

Mismatch negativity generation in subjects at risk for psychosis: source analysis is more sensitive than surface electrodes in risk prediction.

Background: Deficits of mismatch negativity (MMN) in patients with schizophrenia have been demonstrated many times and there is growing evidence that alterations of MMN already exist in individuals at risk for psychosis. The present study examines differences in MMN between subjects fulfilling ultra-high risk (UHR) or only basic symptoms criteria and it addresses the question, if MMN source analysis can improve prediction of transition to psychosis. Methods: The MMN to duration, frequency, and intensity deviants was recorded in 50 healthy controls and 161 individuals at risk for psychosis classified into three subgroups: only basic symptoms (n = 74), only ultra-high risk (n = 13) and persons who fulfill both risk criteria (n = 74). Based on a three-source model of MMN generation, we conducted an MMN source analysis and compared the amplitudes of surface electrodes and sources among the three groups. Results: Significant differences in MMN generation among the four groups were revealed at surface electrodes Cz and C4 (p < 0.05) and at the frontal source (p < 0.001) for duration deviant stimuli. The 15 subjects from the risk groups who subsequently developed a manifest psychosis had a significantly lower MMN amplitude at frontal source (p = 0.019) without showing significant differences at surface electrodes. Low activity at frontal MMN source increased the risk of transition to manifest disease by the factor 3.12 in UHR subjects. Conclusion: MMN activity differed significantly between subjects presenting only basic symptoms and subjects which additionally meet UHR criteria. The largest differences between groups as well as between individuals with and without transition were observed at the frontal source. The present results suggest that source analysis is more sensitive than surface electrodes in psychosis risk prediction by MMN.

Empathy deficits, callous-unemotional traits and structural underpinnings in autism spectrum disorder and conduct disorder youth.

Distinct empathy deficits are often described in patients with conduct disorder (CD) and autism spectrum disorder (ASD) yet their neural underpinnings and the influence of comorbid Callous-Unemotional (CU) traits are unclear. This study compares the cognitive (CE) and affective empathy (AE) abilities of youth with CD and ASD, their potential neuroanatomical correlates, and the influence of CU traits on empathy. Adolescents and parents/caregivers completed empathy questionnaires (N = 148 adolescents, mean age = 15.16 years) and T1 weighted images were obtained from a subsample (N = 130). Group differences in empathy and the influence of CU traits were investigated using Bayesian analyses and Voxel-Based Morphometry with Threshold-Free Cluster Enhancement focusing on regions involved in AE (insula, amygdala, inferior frontal gyrus and cingulate cortex) and CE processes (ventromedial prefrontal cortex, temporoparietal junction, superior temporal gyrus, and precuneus). The ASD group showed lower parent-reported AE and CE scores and lower self-reported CE scores while the CD group showed lower parent-reported CE scores than controls. When accounting for the influence of CU traits no AE deficits in ASD and CE deficits in CD were found, but CE deficits in ASD remained. Across all participants, CU traits were negatively associated with gray matter volumes in anterior cingulate which extends into the mid cingulate, ventromedial prefrontal cortex, and precuneus. Thus, although co-occurring CU traits have been linked to global empathy deficits in reports and underlying brain structures, its influence on empathy aspects might be disorder-specific. Investigating the subdimensions of empathy may therefore help to identify disorder-specific empathy deficits.

Therapeutic drug monitoring in adolescents with anorexia nervosa for safe treatment with adjunct olanzapine.

OBJECTIVE: Medication is commonly used in anorexia nervosa (AN) despite largely missing high grade evidence. Olanzapine (OLZ) is the best-evidenced substance used off-label in this group, with conflicting outcome regarding BMI, clinical and safety parameters. Therefore, it is important to strictly assure quality of treatment with OLZ in AN by using 'Therapeutic Drug Monitoring' according to AGNP-guidelines, including serum levels and adverse drug reactions (ADRs) to support safety for adolescents with AN and attempt to generate an initial age- and disorder-specific therapeutic reference range. METHOD: Sixty-five adolescents with AN (aged 10-18) treated with OLZ (98% female; 97.5% AN-restricting-type) were prospectively observed, ADRs reported, and correlations between dosage and serum levels measured at trough level were calculated, a preliminary therapeutic range defined. RESULTS: Mean dosage of OLZ was 8.15 (SD: 2.91) mg and 0.19 (SD: 0.07) mg/kg respectively, average concentration was 26.57 (SD: 13.46) ng/mL. Correlation between daily dosage/dosage per kg and serum level was 0.72 (**p < 0.001)/0.65 (**p < 0.001), respectively. ADRs with impairment were rare (6.3%). 75% improved clinically (CGI). BMI increased significantly by 1.5 kg/m2 (t = 10.6, p < 0.001). A preliminary therapeutic reference range is 11.9 and 39.9 ng/mL. CONCLUSIONS: OLZ in the hands of specialists is a well-tolerated and safe treatment adjunct for adolescents with AN.