Importance:Meta-analyses of ω-3 fatty acids for depression have reported inconsistent results, and pediatric evidence is sparse. Promotion of unproven supplements may delay evidence-based care. Objective:To evaluate whether adjunctive ω-3 fatty acid supplementation improves outcomes in moderate-to-severe pediatric major depressive disorder (MDD). Design, Setting, and Participants:In a multicenter, double-blind, placebo-controlled randomized clinical trial at 5 Swiss child and adolescent psychiatry centers, 257 youths with MDD were enrolled and randomized between April 28, 2017, and March 24, 2022, and followed up for 36 weeks, with final analysis from July 1, 2022, to January 26, 2023. Analysis was based on intention to treat. Interventions:Participants received ω-3 fatty acids, 1.5 g/d (1 g of eicosapentaenoic acid [EPA] and 0.5 g of docosahexaenoic acid [DHA], 2:1 ratio), or medium-chain triglyceride placebo in combination with standardized psychotherapy. Antidepressant use was permitted per national guidelines. Main Outcomes and Measures:The primary outcome was the trajectory of Children's Depression Rating Scale-Revised (CDRS-R) scores analyzed with a joint mixed-effects and time-to-event model accounting for dropout or initiation of off-trial antidepressant therapy. Secondary outcomes included response (≥30% reduction in CDRS-R scores), remission (CDRS-R score ≤28), self-rated depression, quality of life, suicidality, and safety. Results:Of 257 randomized participants (mean [SD] age, 15.7 [1.7] years; 188 [73.2%] female; mean [SD] CDRS-R score, 58.5 [8.8]), 129 received ω-3 supplements and 128 received placebo. The mean (SD) CDRS-R scores decreased similarly in both groups: at 12 weeks, 45.93 (11.98) vs 46.08 (12.99); at 36 weeks, 36.50 (13.12) vs 36.83 (15.46). The adjusted mean difference in CDRS-R scores was 0.77 (95% CI, -1.39 to 2.93; P = .49) points. The hazard ratio for time to dropout was 1.22 (95% CI, 0.83-1.79; P = .32). Response occurred in 34 of 109 (31.2%) ω-3 recipients vs 43 of 110 (39.1%) placebo recipients at 12 weeks; remission occurred at 36 weeks in 30 of 94 ω-3 recipients (31.9%) vs 37 of 90 (41.1%) placebo recipients (all differences were nonsignificant). Secondary measures and suicidality improved without between-group differences. EPA plus DHA levels expressed by the ω-3 index rose by a mean (SD) of 4.33% (1.54%) and 4.88% (2.38%) at 12 and 36 weeks, respectively, in the ω-3 arm, confirming adherence. A total of 76 serious adverse events were reported in 97 participants, with 31 occurring in the placebo arm and 45 in the ω-3 arm. These included 28 suicide attempts, but no deaths or permanent disabilities. None of these were judged to be causally related to the study medication. Conclusions and Relevance:In this randomized clinical trial, adjunctive ω-3 administration, 1.5 g/d (EPA:DHA, 2:1), did not outperform placebo in youths with MDD. Future work should assess EPA-enriched formulations and biomarker-guided approaches. Trial Registration:ClinicalTrials.gov Identifier: NCT03167307.

INTRODUCTION:Suicidal ideation (SI) is a major public health concern among adolescents. Although parental criticism within the Expressed Emotion (EE) framework has been linked to SI, the impact of a balance between positive and negative interaction remains understudied. This study introduces the Positivity-Negativity Difference of EE (PND-EE), investigates its relationship with SI, and examines whether dimensions of the Interpersonal Theory of Suicide (IPTS) mediate this relationship. METHODS:The study included a combined clinical and population-based sample of 46 adolescents (Mage = 15.37, SDage = 1.37) and their mothers. Participants completed questionnaires assessing SI and the IPTS dimensions Thwarted Belongingness (TB) and Perceived Burdensomeness (PB). Mothers completed the Preschool Five Minute Speech Sample, which has proven suitable for assessing EE in adolescence. Simple and parallel mediation analyses were conducted using Hayes' PROCESS macro. RESULTS:Higher PND-EE was directly associated with lower SI in all analyses. Both TB and PB significantly mediated the effect of PND-EE on SI in simple mediation analyses, but only PB remained statistically significant in the parallel mediation analysis. CONCLUSIONS:Our findings highlight the potential of PND-EE as a promising measure of EE in adolescents. Enhancing positive parent-adolescent interactions and addressing TB and PB in clinical interventions may help reduce adolescent SI.

Introduction:Insight in psychosis has been associated with psychosis remission, treatment compliance and better functioning, but also with depression, increased suicide risk and worse subjective wellbeing. This insight paradox has not been sufficiently studied. Methods:Participants (N = 443) came from the first-episode psychosis OPTiMiSE trial. Insight was assessed with the clinician-rated Positive and Negative Syndrome Scale for Schizophrenia (PANSS)-G12 item. We investigated the cross-sectional associations of insight with clinical measures at baseline and at 4 weeks and the effect of insight change over the 4-week follow-up on outcomes at that point, whilst adjusting for baseline insight and other potential confounders. Results:At baseline and at week 4 better insight was cross-sectionally associated with higher rates of psychosis remission, lower illness severity and better psychosocial functioning (p < .001). At baseline, but not at week 4, better insight was cross-sectionally linked with more severe depressive symptomatology (p = .001), higher suicidality levels (p = .033) and worse subjective wellbeing (p = .022). Insight improvement was associated with higher rates of psychosis remission (p < .001), lower illness severity (p < .001) and better functioning (p = .014) at 4 weeks. Better baseline insight, but not insight change, was related to more severe depression (p < .001) and worse subjective wellbeing (p = .001) at 4 weeks. Conclusions:Insight was cross-sectionally associated with positive and negative clinical measures at baseline, but the latter was not replicated at 4 weeks. Improvement in insight over 4 weeks was not linked with any adverse outcome, offering reassurance to those making efforts to enhance insight early in treatment.

QuestionDoes adding 1.5 g of omega-3 fatty acids to multimodal treatment improve outcomes in children and adolescents with moderate to severe pediatric major depressive disorder (MDD)?FindingsIn a 36-week randomized clinical trial with 257 participants, omega-3 fatty acids showed no significant benefit over placebo in depression severity, response and remission rates, quality of life, or antidepressant use. Adherence was high, and adverse event rates were similar between groups; approximately one-half of participants still met criteria for moderate to severe pediatric MDD despite treatment.MeaningThese findings do not support the use of 1.5 g of omega-3 fatty acids as adjunctive therapy for pediatric MDD. This randomized clinical trial assesses the efficacy of omega-3 fatty acids in reducing depressive symptoms and improving quality of life in children and adolescents with moderate to severe major depressive disorder in Switzerland. ImportanceMeta-analyses of omega-3 fatty acids for depression have reported inconsistent results, and pediatric evidence is sparse. Promotion of unproven supplements may delay evidence-based care.ObjectiveTo evaluate whether adjunctive omega-3 fatty acid supplementation improves outcomes in moderate-to-severe pediatric major depressive disorder (MDD).Design, Setting, and ParticipantsIn a multicenter, double-blind, placebo-controlled randomized clinical trial at 5 Swiss child and adolescent psychiatry centers, 257 youths with MDD were enrolled and randomized between April 28, 2017, and March 24, 2022, and followed up for 36 weeks, with final analysis from July 1, 2022, to January 26, 2023. Analysis was based on intention to treat.InterventionsParticipants received omega-3 fatty acids, 1.5 g/d (1 g of eicosapentaenoic acid [EPA] and 0.5 g of docosahexaenoic acid [DHA], 2:1 ratio), or medium-chain triglyceride placebo in combination with standardized psychotherapy. Antidepressant use was permitted per national guidelines.Main Outcomes and MeasuresThe primary outcome was the trajectory of Children's Depression Rating Scale-Revised (CDRS-R) scores analyzed with a joint mixed-effects and time-to-event model accounting for dropout or initiation of off-trial antidepressant therapy. Secondary outcomes included response (>= 30% reduction in CDRS-R scores), remission (CDRS-R score <= 28), self-rated depression, quality of life, suicidality, and safety.ResultsOf 257 randomized participants (mean [SD] age, 15.7 [1.7] years; 188 [73.2%] female; mean [SD] CDRS-R score, 58.5 [8.8]), 129 received omega-3 supplements and 128 received placebo. The mean (SD) CDRS-R scores decreased similarly in both groups: at 12 weeks, 45.93 (11.98) vs 46.08 (12.99); at 36 weeks, 36.50 (13.12) vs 36.83 (15.46). The adjusted mean difference in CDRS-R scores was 0.77 (95% CI, -1.39 to 2.93; P = .49) points. The hazard ratio for time to dropout was 1.22 (95% CI, 0.83-1.79; P = .32). Response occurred in 34 of 109 (31.2%) omega-3 recipients vs 43 of 110 (39.1%) placebo recipients at 12 weeks; remission occurred at 36 weeks in 30 of 94 omega-3 recipients (31.9%) vs 37 of 90 (41.1%) placebo recipients (all differences were nonsignificant). Secondary measures and suicidality improved without between-group differences. EPA plus DHA levels expressed by the omega-3 index rose by a mean (SD) of 4.33% (1.54%) and 4.88% (2.38%) at 12 and 36 weeks, respectively, in the omega-3 arm, confirming adherence. A total of 76 serious adverse events were reported in 97 participants, with 31 occurring in the placebo arm and 45 in the omega-3 arm. These included 28 suicide attempts, but no deaths or permanent disabilities. None of these were judged to be causally related to the study medication.Conclusions and RelevanceIn this randomized clinical trial, adjunctive omega-3 administration, 1.5 g/d (EPA:DHA, 2:1), did not outperform placebo in youths with MDD. Future work should assess EPA-enriched formulations and biomarker-guided approaches.Trial RegistrationClinicalTrials.gov Identifier: NCT03167307

BACKGROUND:Low concentrations of systemic folates have been associated with a higher risk of major depressive disorder (MDD) and more severe symptoms. Moreover, folate supplementation has been shown to increase the response to selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). Folates reach the brain through the choroid plexus via transcytosis mediated by the folate receptor alpha (FRα). FRα also represents the main mechanism of folate retrieval from the nascent urine. Autoantibodies against the FRα autoantibodies(FRAAs) have been found in the serum of individuals with cerebral folate deficiency. OBJECTIVES:This study aimed to assess the role of serum FRAA titer on serum folate concentration, disease severity, and response to the SSRI/SNRI treatment in adolescents with MDD. METHODS:Serum samples at baseline obtained from the participants of a large multicenter intervention trial in moderately to severely depressed youth were analyzed. Quantification of FRAA was performed by enzyme-linked immunosorbent assay. Serum folate concentration was determined by radioligand binding assay. RESULTS:FRAA titer in the patients with folate deficiency (≤3.0 ng/mL) was significantly higher than that in the patients with a normal folate concentration, and a low FRAA titer was associated with a reduced risk of folate deficiency. No correlation was found between the Children's Depression Rating Scale-Revised score and the serum folate concentration or the FRAA titer. In regression analysis, the effect size of the serum folate concentration on the response to SSRI/SNRI was larger than that of the FRAA titer. The response rate to the treatment in the high-folate group was ∼4 times that in the low-folate group (28.5% compared with 6.7%). CONCLUSIONS:In conclusion, patients with high-FRAA titers carry a higher risk of folate deficiency. Moreover, the response to SSRI/SNRI treatment is less likely in patients with folate deficiency.

Pediatric major depressive disorder (MDD) represents a leading cause of disability worldwide in children and adolescents, while its underlying pathophysiology remains largely elusive. The endocannabinoid system (ECS) and the hypothalamus-pituitary-adrenal (HPA) axis are considered intertwined regulatory systems crucially implicated in the pathophysiology of depressive disorders. This study explores the cross-sectional and longitudinal association between the ECS, specifically anandamide (AEA), and the HPA axis with its main effector cortisol and MDD status and severity in children and adolescents. Utilizing data from the omega-3-pMDD trial, a phase III Randomized Clinical Trial assessing the efficacy and safety of omega-3 fatty acid supplementation in pediatric MDD, we examined hair AEA and cortisol concentrations in 110 children and adolescents aged 8-17 years, with MDD. Associations between MDD, symptom severity and hair AEA and cortisol concentrations were explored across four measurement time points (baseline, week 6, 24 and 36). Additionally, 127 healthy children and adolescents were examined once to enable cross-sectional comparisons between MDD cases and healthy controls. Baseline comparisons for the 237 children and adolescents showed lower cortisol and AEA levels in hair of children and adolescents with MDD compared to healthy controls. Longitudinal multi-level analysis over all time-points further corroborated negative longitudinal associations between hair cortisol and depressive symptoms in children and adolescents with MDD. Taken together, reduced baseline AEA and cortisol levels emerge as robust biomarker in depressed youth, while the negative longitudinal association between hair cortisol and depression symptoms might provide useful for therapy monitoring purposes. These results hold implications for early detection, diagnosis, and therapeutic response prediction in pediatric MDD.

BACKGROUND:Almost 40% of individuals at ultra-high risk (UHR) for psychosis experience persistent attenuated psychotic symptoms (APS) yet it is unclear (1) whether they share overlapping clinical and functional outcomes compared to individuals who transition to psychosis, (2) when symptom and functioning trajectories begin to diverge between UHR individuals with different clinical outcomes, and (3) whether non-remission (persistent APS or transition) can be predicted using baseline and/or longitudinal data. STUDY DESIGN:Participants were drawn from 2 randomized clinical trials: Neurapro (n = 220; discovery sample) and STEP (n = 180; external validation sample). First, 12-24 month symptoms and functioning were compared between UHR individuals with persistent APS, sustained remission, or transition to psychosis. Next, short-term changes in symptoms and functioning were compared between groups to determine timepoints at which trajectories began to diverge. Finally, we used support vector machines to predict non-remission (persistent APS or transition) vs sustained remission using data from baseline, 6-month follow-up, and combined baseline and 6-month follow-up. RESULTS:Individuals with persistent APS had substantially poorer outcomes compared to those who remitted, and more closely resembled individuals who later transitioned to psychosis. Despite few baseline differences between groups, clinical and functional trajectories of the persistent APS and transition groups rapidly diverged from those who remitted. Prediction of non-remission was poor using baseline data but improved substantially when using 6-month follow-up or combined baseline-6-month data. CONCLUSIONS:Ultra-high-risk individuals with persistent APS display similar clinical and functional trajectories to transitioned cases, suggesting that more intensive and sustained intervention is required for this subgroup. However, prospective identification of individuals with poor clinical outcomes (ie, persistence or deterioration of attenuated psychotic symptoms) may require longitudinal monitoring of symptom and functioning trajectories for several months.

Dysregulation of inflammatory mediators and complement cascade proteins has been implicated in psychosis. In the current study, we aimed to investigate the relationship between complement cascade proteins and inflammatory cytokines in blood from people at clinical high risk (CHR) for psychosis and at first episode of psychosis (FEP). Baseline blood samples from two cohorts of CHR participants [NEURAPRO (n = 153) and STEP (n = 146)], and one cohort of FEP patients [OPTiMiSE (n = 226)] were included. The blood levels of three Inflammatory markers including Interleukin (IL)-6, Tumour necrosis factor-alpha (TNF-α) and C-reactive protein (CRP) along with about 30 complement proteins were considered for the analyses. First, we evaluated the interrelationship between the inflammatory markers and then using regression models, we investigated their association with complement proteins. We detected positive associations among all three inflammatory markers IL-6, TNF-α, and CRP in CHR individuals, whereas in FEP positive association was observed only between IL-6 and TNF-α. Regression models showed strong positive associations for complement proteins C3, C4A, C4B, C5, CFB and CFI with all three inflammatory markers in both CHR cohorts. This indicates the presence of a complement related pro-inflammatory tone at risk of developing psychosis. In contrast, in the FEP cohort, complement proteins C1QA, C3, C5, FCN-2, and MASP2 showed an inverse association with TNF-α, and no association found with IL-6 or CRP. These results suggest a switch in the immune activity in the peripheral circulation of FEP compared to CHR. These novel findings propose that complement protein-targeted anti-inflammatory therapy could be effective at CHR state and hence could be used for early intervention in psychosis.

Numerous aspects of depressive symptomatology in first-episode schizophrenia spectrum disorders (FES) remain unclear. Based on data from the FES OPTiMiSE trial, we estimated the prevalence of depression (Calgary Depression Scale for Schizophrenia (CDSS) total score ≥7) at baseline (n = 122, 27.5%) and at weeks 4 (n = 57, 15.9%) and 10 (n = 14, 21.5%). Baseline depression was cross-sectionally associated with more severe extrapyramidal symptoms (p = 0.036) and poorer subjective wellbeing (p < 0.001). At week 4, baseline depression was linked to poorer psychosocial functioning (p < 0.001) and subjective wellbeing (p < 0.001). At week 10, baseline depression was associated with psychosis non-remission (p = 0.042) and worse subjective wellbeing (p = 0.011). There was a significant correlation between decrease in CDSS and PANSS total scores (p < 0.001) at weeks 4 and 10. Depressive symptomatology in the FES OPTiMiSE trial was prevalent and associated with poorer objectively- and subjectively-measured outcomes over a 10-week follow-up. Early intervention for depression may improve outcomes in FES.

OBJECTIVE:Non-adherence is an important factor in clinical trials, which has not been investigated in people at ultra-high risk (UHR) of developing a first episode of psychosis. METHODS:Exploratory analysis of data from NEURAPRO, a multicenter, placebo-controlled trial of long-chain omega-3 polyunsaturated fatty acids (omega-3 PUFAs) in 304 individuals at UHR. We examined correlates of non-adherence with study medication (omega-3 PUFAs or placebo), including patient, illness and treatment factors, plus transition to psychosis. Non-adherence was defined as <75% study medication intake over 6 months and, post hoc, by the number of returned pills. RESULTS:Of 285 randomized participants with baseline fatty acid data, 163 (57.2%) were non-adherent. In univariate analyses, non-adherence was associated with baseline omega-3 index, pre-baseline duration of untreated symptoms, smoking, cannabis use, lower baseline Social and Occupational Functioning Assessment Scale, Global Functioning: Social and Role Scale scores and transition to psychosis. Transition to psychosis risk was significantly lower in the adherent than non-adherent group (4.2%, 95% CI = 0.7-7.7% vs 17.3%, 95% CI = 10.4-24.2%), Kaplan-Meier Log-rank test, chi-square = 10.675, p = 0.001), independent of omega-3 PUFA treatment status. Similarly, Cox regression analysis, covarying for the aforementioned factors significantly associated with non-adherence, also revealed non-adherence as an independent predictor of transition to psychosis (B = 1.452, p = 0.005). Finally, non-adherence was also significantly associated with transition to psychosis, even when defining non-adherence by number of returned pills. CONCLUSION:Non-adherence predicted a higher risk of progressing to psychosis in UHR individuals. Further studies are needed to better understand factors contributing to non-adherence and how non-adherence is related to transition to psychosis.

Introduction:Adolescent suicidality is a significant public health issue. To develop effective interventions aimed at preventing suicide in this vulnerable population, it is essential to understand the complex interplay of health-related quality of life, depression and suicidal ideation. Methods:For this purpose, we analyzed longitudinal data of 250 children and adolescents diagnosed with major depressive disorder (M = 15.7, SD = 1.6, range 8-18 years, 74% females). The main goal of the study was to examine whether the effect of health-related quality of life on individual trajectories of suicidal ideation is mediated by depression severity. A series of t-tests, Chi-squared-tests, Fisher's exact tests and a mediation analysis including three robust linear mixed-effects models were conducted. Results:Depressed adolescents with suicidal ideation reported lower health-related quality of life across physical, psychological, peer, and school domains compared to those without suicidal ideation, while no significant difference was observed in the family-related domain. Psychological well-being emerged as the sole domain of health-related quality of life with a direct influence on suicidal ideation. Notably, depression severity mediated the effect of physical, psychological, peer- and school-related quality of life on suicidal ideation. Discussion:Our findings suggest that improving health-related quality of life reduces depressive symptoms, which in turn leads to lower suicidal ideation. This highlights the importance of including health-related quality of life in the clinical assessment of suicide risk as well as targeting health-related quality of life in therapeutic interventions. In the light of the results of this study, interventions should not only focus on classical clinical criteria of psychiatric diagnoses such as major depressive disorder, but also on broader, more resource-oriented constructs such as health-related quality of life to better mitigate the risk of suicide in this vulnerable population. Clinical Trial Registration:www.ClinicalTrials.gov, identifier [NCT03167307].

Extrapyramidal symptoms (EPS) may occur as a primary feature in patients with first-episode psychosis with no or brief exposure to antipsychotics (AP). We aimed to analyse the prevalence of EPS in naïve and quasi-naïve first episode schizophrenia spectrum disorders (FES), their demographic and clinical correlates at baseline, and their association with clinical outcomes during follow-up. We analysed data from the OPTiMiSE trial, Phase 1 (n = 481 participants with FES, aged 18-40). The presence of EPS was defined as a score on the neurological side effects subscale of the UKU ≥ 1. We compared groups with and without baseline EPS in demographic, clinical and functional measures, and performed logistic and linear regressions models to analyse the associations between baseline EPS and clinical outcomes at follow-up. The prevalence of EPS at baseline was 30 % and was higher in women. There were no differences between AP-naïve or quasi-naïve participants. Participants with EPS showed a higher rate of depressive symptoms and suicidality at baseline. The fully adjusted models showed an association between the presence of EPS at baseline and more severe depressive, positive, negative, general and total symptoms, increased suicidality, and poorer subjective wellbeing and functionality at follow-up. Our findings support EPS as a primary feature of schizophrenia and suggest that early onset EPS (after no or minimal AP exposure) may point to a FES subgroup with poorer clinical prognosis. This suggests the role of EPS as an early marker of poor outcome, with the potential to guide targeted interventions in FES.

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.

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.

The concept of ultra-high risk for psychosis (UHR) has been at the forefront of psychiatric research for several decades, with the ultimate goal of preventing the onset of psychotic disorder in high-risk individuals. Orygen (Melbourne, Australia) has led a range of observational and intervention studies in this clinical population. These datasets have now been integrated into the UHR 1000+ cohort, consisting of a sample of 1,245 UHR individuals with a follow-up period ranging from 1 to 16.7 years. This paper describes the cohort, presents a clinical prediction model of transition to psychosis in this cohort, and examines how predictive performance is affected by changes in UHR samples over time. We analyzed transition to psychosis using a Cox proportional hazards model. Clinical predictors for transition to psychosis were investigated in the entire cohort using multiple imputation and Rubin's rule. To assess performance drift over time, data from 1995-2016 were used for initial model fitting, and models were subsequently validated on data from 2017-2020. Over the follow-up period, 220 cases (17.7%) developed a psychotic disorder. Pooled hazard ratio (HR) estimates showed that the Comprehensive Assessment of At-Risk Mental States (CAARMS) Disorganized Speech subscale severity score (HR=1.12, 95% CI: 1.02-1.24, p=0.024), the CAARMS Unusual Thought Content subscale severity score (HR=1.13, 95% CI: 1.03-1.24, p=0.009), the Scale for the Assessment of Negative Symptoms (SANS) total score (HR=1.02, 95% CI: 1.00-1.03, p=0.022), the Social and Occupational Functioning Assessment Scale (SOFAS) score (HR=0.98, 95% CI: 0.97-1.00, p=0.036), and time between onset of symptoms and entry to UHR service (log transformed) (HR=1.10, 95% CI: 1.02-1.19, p=0.013) were predictive of transition to psychosis. UHR individuals who met the brief limited intermittent psychotic symptoms (BLIPS) criteria had a higher probability of transitioning to psychosis than those who met the attenuated psychotic symptoms (APS) criteria (HR=0.48, 95% CI: 0.32-0.73, p=0.001) and those who met the Trait risk criteria (a first-degree relative with a psychotic disorder or a schizotypal personality disorder plus a significant decrease in functioning during the previous year) (HR=0.43, 95% CI: 0.22-0.83, p=0.013). Models based on data from 1995-2016 displayed good calibration at initial model fitting, but showed a drift of 20.2-35.4% in calibration when validated on data from 2017-2020. Large-scale longitudinal data such as those from the UHR 1000+ cohort are required to develop accurate psychosis prediction models. It is critical to assess existing and future risk calculators for temporal drift, that may reduce their utility in clinical practice over time.

ObjectiveTo 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.MethodsIn 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.ResultsNo 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.ConclusionOur 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.

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.

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.

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.