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.

The association of plasma inflammatory markers with omega-3 fatty acids and their mediating role in psychotic symptoms and functioning: An analysis of the NEURAPRO clinical trial.

BACKGROUND: There is increasing evidence that dysregulation of polyunsaturated fatty acids (FAs) mediated membrane function plays a role in the pathophysiology of schizophrenia. Even though preclinical findings have supported the anti-inflammatory properties of omega-3 FAs on brain health, their biological roles as anti-inflammatory agents and their therapeutic role on clinical symptoms of psychosis risk are not well understood. In the current study, we investigated the relationship of erythrocyte omega-3 FAs with plasma immune markers in a clinical high risk for psychosis (CHR) sample. In addition, a mediation analysis was performed to examine whether previously reported associations between omega-3 FAs and clinical outcomes were mediated via plasma immune markers. Clinical outcomes for CHR participants in the NEURAPRO clinical trial were measured using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Scale of Assessment of Negative Symptoms (SANS) and Social and Occupational Functioning Assessment Scale (SOFAS) scales. The erythrocyte omega-3 index [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] and plasma concentrations of inflammatory markers were quantified at baseline (n = 268) and 6 month follow-up (n = 146) by gas chromatography and multiplex immunoassay, respectively. In linear regression models, the baseline plasma concentrations of Interleukin (IL)-15, Intercellular adhesion molecule (ICAM)-1 and Vascular cell adhesion molecule (VCAM)-1 were negatively associated with baseline omega-3 index. In addition, 6-month change in IL-12p40 and TNF-α showed a negative association with change in omega-3 index. In longitudinal analyses, the baseline and 6 month change in omega-3 index was negatively associated with VCAM-1 and TNF-α respectively at follow-up. Mediation analyses provided little evidence for mediating effects of plasma immune markers on the relationship between omega-3 FAs and clinical outcomes (psychotic symptoms and functioning) in CHR participants. Our results indicate a predominantly anti-inflammatory relationship of omega-3 FAs on plasma inflammatory status in CHR individuals, but this did not appear to convey clinical benefits at 6 month and 12 month follow-up. Both immune and non-immune biological effects of omega-3 FAs would be resourceful in understanding the clinical benefits of omega-3 FAs in CHR papulation.

Machine learning based prediction and the influence of complement - Coagulation pathway proteins on clinical outcome: Results from the NEURAPRO trial.

BACKGROUND: Functional outcomes are important measures in the overall clinical course of psychosis and individuals at clinical high-risk (CHR), however, prediction of functional outcome remains difficult based on clinical information alone. In the first part of this study, we evaluated whether a combination of biological and clinical variables could predict future functional outcome in CHR individuals. The complement and coagulation pathways have previously been identified as being of relevance to the pathophysiology of psychosis and have been found to contribute to the prediction of clinical outcome in CHR participants. Hence, in the second part we extended the analysis to evaluate specifically the relationship of complement and coagulation proteins with psychotic symptoms and functional outcome in CHR. MATERIALS AND METHODS: We carried out plasma proteomics and measured plasma cytokine levels, and erythrocyte membrane fatty acid levels in a sub-sample (n = 158) from the NEURAPRO clinical trial at baseline and 6 months follow up. Functional outcome was measured using Social and Occupational Functional assessment Score (SOFAS) scale. Firstly, we used support vector machine learning techniques to develop predictive models for functional outcome at 12 months. Secondly, we developed linear regression models to understand the association between 6-month follow-up levels of complement and coagulation proteins with 6-month follow-up measures of positive symptoms summary (PSS) scores and functional outcome. RESULTS AND CONCLUSION: A prediction model based on clinical and biological data including the plasma proteome, erythrocyte fatty acids and cytokines, poorly predicted functional outcome at 12 months follow-up in CHR participants. In linear regression models, four complement and coagulation proteins (coagulation protein X, Complement C1r subcomponent like protein, Complement C4A & Complement C5) indicated a significant association with functional outcome; and two proteins (coagulation factor IX and complement C5) positively associated with the PSS score. Our study does not provide support for the utility of cytokines, proteomic or fatty acid data for prediction of functional outcomes in individuals at high-risk for psychosis. However, the association of complement protein levels with clinical outcome suggests a role for the complement system and the activity of its related pathway in the functional impairment and positive symptom severity of CHR patients.

Home treatment as an add-on to family-based treatment in adolescents with anorexia nervosa: A pilot study.

OBJECTIVE: This pilot study examines the feasibility and the effectiveness of add-on home treatment (HT) to family-based treatment (FBT) in adolescents with anorexia nervosa (AN). The HT intervention is delivered by specialised nurses and aims at supporting patients and parents to re-establish family meals in the home environment. METHOD: We performed a 3-month study in AN patients with a waiting-list control design comparing 45 (43 females, 2 males) adolescents receiving FBT augmented with HT compared to 22 (21 females, 1 male) participants receiving FBT alone on the waiting list for additional HT. Eating disorder diagnosis, psychopathology and severity of clinical symptoms were assessed using the Eating Disorder Examination (EDE) interview, the Eating Disorders Inventory (EDI-2) and clinical parameters (BMI, menstrual status, level of over-exercising) at baseline and after 3 months. RESULTS: After 3 months of treatment, both treatment groups showed a significant early weight gain, a reduction in the rate of AN diagnoses assessed with the EDE interview and a reduction in EDI-2 total scores. The combined HT/FBT group showed a significantly greater increase in BMI than the FBT-only group. In the combined HT/FBT group, none of the patients had to be admitted to hospital, while three (13.6%) of the FBT-only group had to be referred to inpatient treatment. DISCUSSION: Our results suggest that HT augmented FBT might be useful compared to FBT alone in terms of early weight gain and might reduce the risk of hospital admission in adolescent AN.

[AdoASSIP, a novel therapeutic tool for the prevention of youth suicide]. / AdoASSIP: un nouvel outil thérapeutique dans la prévention du suicide des jeunes.

Suicide is the leading cause of death among Swiss adolescents. Often, a suicide attempt is the outcome of a "suicidal process" at the end of which death is perceived as the only means of escaping from intolerable psychic pain. A suicide attempt entails a high risk of repetition. AdoASSIP, a brief adjunctive therapy adapted for adolescents, which is being implemented in Switzerland, specifically aims at reducing that risk. Starting from the story of the suicide attempt told by the adolescent, patient and therapist jointly try to better understand the "logic" of the suicidal process. Short-term and long-term needs, as well as warning-signs of a crisis are identified, and a safety plan is developed. AdoASSIP is now available in the cantons of Geneva and Vaud.

Le suicide est la première cause de mortalité chez les adolescents suisses. Une tentative de suicide est souvent l'issue d'un «processus suicidaire¼ au terme duquel la mort est perçue comme seul moyen d'échapper à une douleur psychique intolérable. Une tentative de suicide comporte un risque important de réitération. AdoASSIP, une thérapie brève adjonctive adaptée pour les adolescents, qui est en cours d'implantation en Suisse, vise spécifiquement à diminuer ce risque. À partir du récit de la tentative de suicide racontée par l'adolescent, patient et thérapeute essayent conjointement de mieux comprendre la «logique¼ du processus suicidaire. Les besoins clés à court et long termes, ainsi que les signaux d'alerte d'une crise, sont identifiés et un plan de sécurité est élaboré. AdoASSIP est désormais disponible dans les cantons de Genève et Vaud.

Feasibility and acceptability of home treatment as an add-on to family based therapy for adolescents with anorexia nervosa. A case series.

OBJECTIVE: This study examines the feasibility, acceptability, and preliminary effect sizes on outcome measures of home treatment (HT) as an add-on to family-based therapy (FBT) in adolescents with anorexia nervosa (AN). The HT intervention is delivered by specialized nurses and aims at supporting patients and parents to re-establish family meals in the home environment. METHOD: Forty-five (43 female, 2 male) adolescents meeting ICD 10 criteria for anorexia nervosa or atypical anorexia nervosa received FBT augmented with HT over 12 weeks. Eating disorder (ED) diagnosis, psychopathology and severity of clinical symptoms were assessed using the Eating Disorder Examination (EDE) interview, the Eating Disorders Inventory (EDI-2) at baseline (BL) and after 3-months RESULTS: All participants and parents were retained and found HT acceptable. At the end of Treatment (EOT) participants showed a significant early weight gain, a reduction in the AN psychopathology assessed with the EDE interview and a reduction in EDI-2 total scores. None of the patients had to be admitted to hospital. Treatment satisfaction was high in both patients and parents. DISCUSSION: Findings provide preliminary evidence that HT is feasible, acceptable and produces clinically significant improvements in targeted outcome.

The association between migrant status and transition in an ultra-high risk for psychosis population.

PURPOSE: Migrant status is one of the most replicated and robust risk factors for developing a psychotic disorder. This study aimed to determine whether migrant status in people identified as Ultra-High Risk for Psychosis (UHR) was associated with risk of transitioning to a full-threshold psychotic disorder. METHODS: Hazard ratios for the risk of transition were calculated from five large UHR cohorts (n = 2166) and were used to conduct a meta-analysis using the generic inverse-variance method using a random-effects model. RESULTS: 2166 UHR young people, with a mean age of 19.1 years (SD ± 4.5) were included, of whom 221 (10.7%) were first-generation migrants. A total of 357 young people transitioned to psychosis over a median follow-up time of 417 days (I.Q.R.147-756 days), representing 17.0% of the cohort. The risk of transition to a full-threshold disorder was not increased for first-generation migrants, (HR = 1.08, 95% CI 0.62-1.89); however, there was a high level of heterogeneity between studies The hazard ratio for second-generation migrants to transition to a full-threshold psychotic disorder compared to the remainder of the native-born population was 1.03 (95% CI 0.70-1.51). CONCLUSIONS: This meta-analysis did not find a statistically significant association between migrant status and an increased risk for transition to a full-threshold psychotic disorder; however, several methodological issues could explain this finding. Further research should focus on examining the risk of specific migrant groups and also ensuring that migrant populations are adequately represented within UHR clinics.

Disentangling the Molecular Mechanisms of the Antidepressant Activity of Omega-3 Polyunsaturated Fatty Acid: A Comprehensive Review of the Literature.

Major depressive disorders (MDDs) are often associated with a deficiency in long-chain omega-3 polyunsaturated fatty acids (ω-3 PUFAs), as well as signs of low-grade inflammation. Epidemiological and dietary studies suggest that a high intake of fish, the major source of ω-3 PUFAs, is associated with lower rates of MDDs. Meta-analyses of randomized placebo-controlled ω-3 PUFAs intervention-trials suggest that primarily eicosapentaenoic acid (EPA), but not docosahexaenoic acid (DHA), is responsible for the proposed antidepressant effect. In this review, we dissect the current biological knowledge on EPA and DHA and their bioactive lipid metabolites to search for a pharmacological explanation of this, to date, unexplained clinical observation. Through enzymatic conversion by cyclooxygenase (COX), lipoxygenase (ALOX), and cytochrome P-450 monooxygenase (CYP), EPA and DHA are metabolized to major anti-inflammatory and pro-resolving lipid mediators. In addition, both ω-3 PUFAs are precursors for endocannabinoids, with known effects on immunomodulation, neuroinflammation, food intake and mood. Finally, both ω-3 PUFAs are crucial for the structure and organization of membranes and lipid rafts. While most biological effects are shared by these two ω-3 PUFAs, some distinct features could be identified: (1) The preferential CYP monooxygenase pathway for EPA and EPA derived eicosanoids; (2) The high CB2 receptor affinities of EPA-derived EPEA and its epoxy-metabolite 17,18-EEQ-EA, while the DHA-derived endocannabinoids lack such receptor affinities; (3) The competition of EPA but not DHA with arachidonic acid (AA) for particular glycerophospholipids. EPA and AA are preferentially incorporated into phosphatidylinositols, while DHA is mainly incorporated into phosphatidyl-ethanolamine, -serine and -choline. We propose that these distinct features may explain the superior antidepressant activity of EPA rich ω-3 PUFAs and that these are potential novel targets for future antidepressant drugs.

ADHD: Current Concepts and Treatments in Children and Adolescents.

Attention deficit hyperactivity disorder (ADHD) is among the most frequent disorders within child and adolescent psychiatry, with a prevalence of over 5%. Nosological systems, such as the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and the International Classification of Diseases, editions 10 and 11 (ICD-10/11) continue to define ADHD according to behavioral criteria, based on observation and on informant reports. Despite an overwhelming body of research on ADHD over the last 10 to 20 years, valid neurobiological markers or other objective criteria that may lead to unequivocal diagnostic classification are still lacking. On the contrary, the concept of ADHD seems to have become broader and more heterogeneous. Thus, the diagnosis and treatment of ADHD are still challenging for clinicians, necessitating increased reliance on their expertise and experience. The first part of this review presents an overview of the current definitions of the disorder (DSM-5, ICD-10/11). Furthermore, it discusses more controversial aspects of the construct of ADHD, including the dimensional versus categorical approach, alternative ADHD constructs, and aspects pertaining to epidemiology and prevalence. The second part focuses on comorbidities, on the difficulty of distinguishing between "primary" and "secondary" ADHD for purposes of differential diagnosis, and on clinical diagnostic procedures. In the third and most prominent part, an overview of current neurobiological concepts of ADHD is given, including neuropsychological and neurophysiological researches and summaries of current neuroimaging and genetic studies. Finally, treatment options are reviewed, including a discussion of multimodal, pharmacological, and nonpharmacological interventions and their evidence base.

[The Zurich Specialist Clinic for Adolescent with Gender Dysphoria - Preliminary Follow-up Results]. / Zürcher Sprechstunde für Jugendliche mit Genderdysphorie ­ erste Verlaufsergebnisse.

The Zurich Specialist Clinic for Adolescent with Gender Dysphoria - Preliminary Follow-up Results The specialist clinic for children and adolescents with gender dysphoria (GD) of the Psychiatric University Hospital of Zurich shows an increasing number of referrals since its foundation in 2009. Since 2014 we started an observational study including adolescents aged 13 years and older. At the time of the first appointment (T0) N = 77 participants completed a battery of questionnaires assessing demographic factors, general psychopathology, quality of life as well as gender identity, social transitioning and GD treatment modalities. Few of the adolescents were socially transitioned and had hormone therapy but 77.9 % wished to get hormone therapy. Follow up assessment T1 was performed after at least one year of treatment in our specialist clinic. 51 adolescents completed an online follow-up examination including the same questionnaires and baseline parameters as well as a scale measuring treatment satisfaction. At T0, 77.3 % of the adolescents scored in the clinical range of the Youth Self Report (YSR) total score, which did not decrease significantly until T1 in our preliminary follow up sample. Puberty blocking before T0 correlated negatively with the YSR score, indicating less psychopathology in treated patients. Preliminary longitudinal analysis suggests that social transitioning influences quality of life (Kidscreen subscale autonomy and parental relationship). At T1, 52 % of the adolescents were socially transitioned in all contexts and 70 % received gender affirming hormonal treatment. Gender identity changed between T0 and T1 in about 18 % of the cases. Treatment satisfaction in most cases was high.

Anxious depression as a clinically relevant subtype of pediatric major depressive disorder.

In adults, anxious depression has been identified as a more severe form of major depressive disorder (MDD), associated with higher depression severity, more suicidal ideation and worse treatment outcome. Research in pediatric depression, however, has been sparse. 126 children and adolescents aged 8-18 years with a primary diagnosis of MDD were categorized into a MDD-only group and an anxious depression group based on clinically elevated scores on the Beck Anxiety Inventory. One-third of the sample was classified as having anxious depression with females being overrepresented in the anxious depressed compared to the MDD-only group. 42.2% of the anxious depressed youth met diagnostic criteria for a comorbid anxiety disorder. Anxious depressed youth were more likely to suffer recurrent depressive episodes, showed higher depression severity and a unique pattern of depressive symptoms characterized by more severe sleep problems, more somatic complaints, more severely depressed mood and more frequent suicidal ideations. Scores on a suicidal ideation scale were increased even when controlling for overall depression severity. However, when comparing depressed patients with and without comorbid anxiety disorders, no differences in depression severity, symptom patterns or suicidal ideations were observed. The results indicate that high anxiety levels in depressed youth are clinically relevant, and given the increase in suicidal ideation, anxiety symptoms during depressive episodes should routinely be screened in clinical practice even in the absence of a fully formed comorbid anxiety disorder.

Opening the Black Box of Cognitive-Behavioural Case Management in Clients with Ultra-High Risk for Psychosis.

BACKGROUND: Cognitive-behavioural therapy (CBT) is the first-choice treatment in clients with ultra-high risk (UHR) for psychosis. However, CBT is an umbrella term for a plethora of different strategies, and little is known about the association between the intensity and content of CBT and the severity of symptomatic outcome. METHODS: A sample of 268 UHR participants received 6 months of CBT with case management (CBCM) in the context of the multi-centre NEURAPRO trial with monthly assessments of attenuated psychotic symptoms (APS). Using multilevel regressions and controlling for the initial severity of APS, the associations between (1) number of CBCM sessions received and severity of APS and (2) specific CBCM components and severity of APS were investigated. RESULTS: In month 1, a higher number of sessions and more assessment of symptoms predicted an increase in APS, while in month 3, a higher number of sessions and more monitoring predicted a decrease in the level of APS. More therapeutic focus on APS predicted an overall increase in APS. CONCLUSIONS: Our findings indicate that the association between intensity/content of CBCM and severity of APS in a sample of UHR participants depends on the length of time in treatment. CBCM may positively impact the severity of APS later in the course of treatment. Therefore, it would seem important to keep UHR young people engaged in treatment beyond this initial period. Regarding the specific content of CBCM, a therapeutic focus on APS may not necessarily be beneficial in reducing the severity of APS, a possibility in need of further investigation.

Ventricular volumes across stages of schizophrenia and other psychoses.

OBJECTIVE: Ventricular enlargement is common in established schizophrenia; however, data from ultra high-risk for psychosis and first-episode psychosis studies are inconclusive. This study aims to investigate ventricular volumes at different stages of psychosis. METHODS: Ventricular volumes were measured using a semi-automated and highly reliable method, for 89 established schizophrenia, 162 first-episode psychosis, 135 ultra high-risk for psychosis and 87 healthy controls using 1.5T magnetic resonance images. Clinical outcome diagnoses for ultra high-risk for psychosis were evaluated at long-term follow-up (mean: 7.5 years). RESULTS: Compared to controls, we identified significant ventricular enlargement of 36.2% in established schizophrenia ( p < 0.001). Ventricular enlargement was not significant in first-episode psychosis (6%) or ultra high-risk for psychosis (-3%). Examination across stages of schizophrenia-spectrum diagnoses subgroups revealed a significant linear trend ( p = 0.006; established schizophrenia = 36.2%, first-episode psychosis schizophrenia = 18.5%, first-episode psychosis schizophreniform = -4.2% and ultra high-risk for psychosis-schizophrenia converters = -18.5%). CONCLUSION: Ventricular enlargement is apparent in patients with established schizophrenia but is not a feature at the earliest stages of illness (ultra high-risk for psychosis and first-episode psychosis). Further research is needed to fully characterize the nature and timing of ventricular volume changes early in the course of illness and how these changes impact outcomes.

[Prevention and interventions for suicidal youth considerations for health professionionals in Switzerland]. / Suizidalität bei Adoleszenten - Prävention und Behandlung.

Adolescence is associated with a dramatic surge in suicide rate. While worldwide age-adjusted suicides rate per 100'000 in under 14-year olds are relatively low around 0.6, a dramatic increase to 7.4 can be observed in 15 ­ 19 year olds with suicide being one of the three leading causes of mortality in most countries in this age group. From 2000 to 2013 the Swiss annual average of completed suicides in 15 ­ 19 year olds was 33.1 (minimum 24; maximum 47). This corresponds to an average age-specific death rate of 7.6, which is slightly above the global mean. Suicide prevention and treatment of suicidality in adolescents is a complex underpinning. Subjectively experienced feelings of insufficiency, hopelessness and the feeling of worthlessness combined with concrete suicidal ideations and the capacity to act out are important indicators for assessing suicidal risk. Suicide attempts as the strongest risk factor for suicide should always be taken seriously, even if they occur in the context of situational crisis. Narcissistic personality traits or increased impulsivity are further indicators of risk. The early detection and effective treatment of mental disorders such as depression, anxiety disorders, bipolar-affective disorders or psychotic disorders provide a great opportunity to reduce the frequency of suicide attempts and suicide. Particular caution is required when co-morbid addictions are present. The maintenance or establishment of sustainable relationships with significant others is considered a key protecting factor. Increasing withdrawal from significant others is an important warning sign and needs urgent involvement of experts. In acute suicidality, the admission to a psychiatric hospital must be considered, if necessary against the will of affected adolescent and their relatives. Personality-related recurrent suicidal behavior requires specific treatment approaches taking into account the prevention of iatrogenic worsening of suicidal patterns.

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.

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.

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.

An open label pilot trial of low-dose lithium for young people at ultra-high risk for psychosis.

AIM: Lithium, even at low doses, appears to offer neuroprotection against a wide variety of insults. In this controlled pilot, we examined the safety (i.e., side-effect profile) of lithium in a sample of young people identified at ultra-high risk (UHR) for psychosis. The secondary aim was to explore whether lithium provided a signal of clinical efficacy in reducing transition to psychosis compared with treatment as usual (TAU). METHODS: Young people attending the PACE clinic at Orygen, Melbourne, were prescribed a fixed dose (450 mg) of lithium (n = 25) or received TAU (n = 78). The primary outcome examined side-effects, with transition to psychosis, functioning and measures of psychopathology assessed as secondary outcomes. RESULTS: Participants in both groups were functionally compromised (lithium group GAF = 56.6; monitoring group GAF = 56.9). Side-effect assessment indicated that lithium was well-tolerated. 64% (n = 16) of participants in the lithium group were lithium-adherent to week 12. Few cases transitioned to psychosis across the study period; lithium group 4% (n = 1); monitoring group 7.7% (n = 6). There was no difference in time to transition to psychosis between the groups. No group differences were observed in other functioning and symptom domains, although all outcomes improved over time. CONCLUSIONS: With a side-effect profile either comparable to, or better than UHR antipsychotic trials, lithium might be explored for further research with UHR young people. A definitive larger trial is needed to determine the efficacy of lithium in this cohort.

Proteomic Biomarkers for the Prediction of Transition to Psychosis in Individuals at Clinical High Risk: A Multi-cohort Model Development Study.

Psychosis risk prediction is one of the leading challenges in psychiatry. Previous investigations have suggested that plasma proteomic data may be useful in accurately predicting transition to psychosis in individuals at clinical high risk (CHR). We hypothesized that an a priori-specified proteomic prediction model would have strong predictive accuracy for psychosis risk and aimed to replicate longitudinal associations between plasma proteins and transition to psychosis. This study used plasma samples from participants in 3 CHR cohorts: the North American Prodrome Longitudinal Studies 2 and 3, and the NEURAPRO randomized control trial (total n = 754). Plasma proteomic data were quantified using mass spectrometry. The primary outcome was transition to psychosis over the study follow-up period. Logistic regression models were internally validated, and optimism-corrected performance metrics derived with a bootstrap procedure. In the overall sample of CHR participants (age: 18.5, SD: 3.9; 51.9% male), 20.4% (n = 154) developed psychosis within 4.4 years. The a priori-specified model showed poor risk-prediction accuracy for the development of psychosis (C-statistic: 0.51 [95% CI: 0.50, 0.59], calibration slope: 0.45). At a group level, Complement C8B, C4B, C5, and leucine-rich α-2 glycoprotein 1 (LRG1) were associated with transition to psychosis but did not surpass correction for multiple comparisons. This study did not confirm the findings from a previous proteomic prediction model of transition from CHR to psychosis. Certain complement proteins may be weakly associated with transition at a group level. Previous findings, derived from small samples, should be interpreted with caution.

Sleep disturbance, but not depression severity, is associated with inflammation in children and adolescents.

STUDY OBJECTIVES: We aimed to examine the association between self-rated and clinician-rated sleep disturbances and C-reactive protein (CRP), an objective marker of inflammation, in pediatric depression. METHODS: Two hundred fifty-six children and adolescents (15.2 ± 1.6 y, 72.3% female) with moderate to severe symptoms of depression participated in the study. Sleep disturbances were assessed by self-reports (Insomnia Severity Index) and clinician ratings (Kiddie-Schedule for Affective Disorder and Schizophrenia), inflammation by plasma CRP levels. RESULTS: Higher levels of CRP correlated positively with clinician-rated middle insomnia and hypersomnia. After adjusting for control variables (body mass index, tobacco, alcohol, stress, age, sex, antidepressants, sleep medication, depression severity), regression models confirmed the significant association of clinician-rated hypersomnia and middle insomnia symptoms with elevated CRP levels. In the adjusted regression models, other clinician-rated manifestations of sleep disturbance (eg, initial insomnia) and insomnia self-ratings were not significantly associated with CRP. Body mass index correlated positively with CRP, but body mass index had no mediating effect on the associations between sleep disturbances and CRP. We did not find an association between depression severity, assessed by the Children's Depression Rating Scale-Revised, and CRP. CONCLUSIONS: Results of the present study indicate a significant association of hypersomnia and middle insomnia symptoms with CRP in pediatric depression, not linked to alterations in the body mass index. CITATION: Strumberger MA, Häberling I, Emery S, et al. Sleep disturbance, but not depression severity, is associated with inflammation in children and adolescents. J Clin Sleep Med. 2023;19(10):1775-1784.