Adjunctive canakinumab reduces peripheral inflammation markers and improves positive symptoms in people with schizophrenia and inflammation: A randomized control trial.

BACKGROUND: Clinical trials of anti-inflammatories in schizophrenia do not show clear and replicable benefits, possibly because patients were not recruited based on elevated inflammation status. Interleukin 1-beta (IL-1ß) mRNA and protein levels are increased in serum, plasma, cerebrospinal fluid, and brain of some chronically ill patients with schizophrenia, first episode psychosis, and clinical high-risk individuals. Canakinumab, an approved anti-IL-1ß monoclonal antibody, interferes with the bioactivity of IL-1ß and interrupts downstream signaling. However, the extent to which canakinumab reduces peripheral inflammation markers, such as, high sensitivity C-reactive protein (hsCRP) and symptom severity in schizophrenia patients with inflammation is unknown. TRIAL DESIGN: We conducted a randomized, placebo-controlled, double-blind, parallel groups, 8-week trial of canakinumab in chronically ill patients with schizophrenia who had elevated peripheral inflammation. METHODS: Twenty-seven patients with schizophrenia or schizoaffective disorder and elevated peripheral inflammation markers (IL-1ß, IL-6, hsCRP and/or neutrophil to lymphocyte ratio: NLR) were randomized to a one-time, subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive antipsychotic treatment. Peripheral blood hsCRP, NLR, IL-1ß, IL-6, IL-8 levels were measured at baseline (pre injection) and at 1-, 4- and 8-weeks post injection. Symptom severity was assessed at baseline and 4- and 8-weeks post injection. RESULTS: Canakinumab significantly reduced peripheral hsCRP over time, F(3, 75) = 5.16, p = 0.003. Significant hsCRP reductions relative to baseline were detected only in the canakinumab group at weeks 1, 4 and 8 (p's = 0.0003, 0.000002, and 0.004, respectively). There were no significant hsCRP changes in the placebo group. Positive symptom severity scores were significantly reduced at week 8 (p = 0.02) in the canakinumab group and week 4 (p = 0.02) in the placebo group. The change in CRP between week 8 and baseline (b = 1.9, p = 0.0002) and between week 4 and baseline (b = 6.0, p = 0.001) were highly significant predictors of week 8 change in PANSS Positive Symptom severity scores. There were no significant changes in negative symptoms, general psychopathology or cognition in either group. Canakinumab was well tolerated and only 7 % discontinued. CONCLUSIONS: Canakinumab quickly reduces peripheral hsCRP serum levels in patients with schizophrenia and inflammation; after 8 weeks of canakinumab treatment, the reductions in hsCRP are related to reduced positive symptom severity. Future studies should consider increased doses or longer-term treatment to confirm the potential benefits of adjunctive canakinumab in schizophrenia. Australian and New Zealand Clinical Trials Registry number: ACTRN12615000635561.

Higher striatal glutamate in male youth with internet gaming disorder.

Internet gaming disorder (IGD) was included in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as a research diagnosis, but little is known about its pathophysiology. Alterations in frontostriatal circuits appear to play a critical role in the development of addiction. Glutamate is considered an essential excitatory neurotransmitter in addictive disorders. This study's aim was to investigate striatal glutamate in youth with IGD compared to healthy controls (HC). Using a cross-sectional design, 25 adolescent male subjects fulfilling DSM-5 criteria for IGD and 26 HC, matched in age, education, handedness and smoking, were included in the analysis. A structural MPRAGE T1 sequence followed by a single-voxel magnetic resonance spectroscopy MEGA-PRESS sequence (TR = 1500 ms, TE = 68 ms, 208 averages) with a voxel size of 20 mm3 were recorded on 3 T Siemens Magnetom Prisma scanner. The voxel was placed in the left striatum. Group comparison of the relative glutamate and glutamine (Glx) was calculated using regression analysis. IGD subjects met an average of 6.5 of 9 DSM-5 IGD criteria and reported an average of 29 h of weekly gaming. Regression analysis showed a significant group effect for Glx, with higher Glx levels in IGD as compared to HC (coef. = .086, t (50) = 2.17, p = .035). Our study is the first to show higher levels of Glx in the striatum in youth with IGD. The elevation of Glx in the striatum may indicate hyperactivation of the reward system in IGD. Thus, results confirm that neurochemical alterations can be identified in early stages of behavioral addictions.

Childhood Maltreatment and Its Association with Cognitive Ability in Young People Suspected to Be at Clinical High Risk of Psychosis.

INTRODUCTION: Childhood maltreatment is associated with both reduced cognitive functioning and the development of psychotic symptoms. However, the specific relationship between childhood maltreatment, cognitive abilities and (pre)psychotic symptoms remains unclear. Therefore, the aim of this study was to investigate the association between childhood maltreatment and tasks of verbal memory and processing speed in a help-seeking sample of an early detection of psychosis service. METHODS: A total of 274 participants consisting of 177 clinical high risk (CHR) for psychosis subjects and 97 clinical controls (CC) with subthreshold CHR underwent a battery of neurocognitive assessments measuring the latent variables verbal memory and processing speed. Additionally, the Trauma and Distress Scale (TADS) was administered to assess varying childhood maltreatment subtypes. Structural equation modeling (SEM) was used to examine associations between verbal memory, processing speed, and maltreatment subtypes. Other factors in the model were age, gender, clinical group (CHR or CC), and the presence of different CHR criteria. RESULTS: Physical abuse was associated with lower scores in verbal memory and processing speed. The explained variance in the SEM reached up to 9.5% for verbal memory and 24.9% for processing speed. Both latent variables were each associated with the presence of cognitive-perceptive basic symptoms. Lower verbal memory was additionally associated with the clinical high-risk group, and processing speed capacity was associated with higher age and female gender. CONCLUSION: Childhood physical abuse in particular was associated with poorer performance on verbal memory and processing speed across both groups of CHR and CC with subthreshold CHR symptoms. This adds to the current literature on reduced cognitive abilities when childhood maltreatment had occurred, albeit subtype dependent. Our findings, together with high prevalence rates of childhood maltreatment in patients with psychosis or CHR states, along with the presence of cognitive deficits in these patients, highlight the importance of not only assessing cognition but also childhood maltreatment in managing these patients. Future research should investigate the specific biological mechanisms of childhood maltreatment on verbal memory and processing speed in CHR subjects, as neurobiological alterations might explain the underlying mechanisms.

Treatment outcome of an intensive psychiatric home treatment for children and adolescents: a non-randomized controlled pilot evaluation.

Home treatment (HT) may offer an effective and cost-efficient alternative to inpatient treatment for children and adolescents with acute mental disorders. This study introduces and evaluates a pilot HT project from Bern, Switzerland, with HT completely replacing an inpatient treatment. A total of n = 133 children and adolescents with acute mental disorders and inpatient treatment needs were treated either in the new HT program (n = 37) or in an active control group with inpatient treatment as usual (I-TAU, n = 96). Psychopathological burden was assessed by the Health of the Nation Outcome Scale for Children and Adolescents clinician-rated (HoNOSCA) and self-rated (HoNOSCA-SR) at the time of admission and at discharge. Treatment effects were assessed and compared using Augmented Inverse Probability Weights to adjust for baseline differences and to control for treatment duration. Participants ranged in age from 6 to 17 years (M = 13.71 years, SD = 2.93), 54% were female. HT resulted in significant improvements in the HoNOSCA (d = 0.79, p < .001) and HoNOSCA-SR (d = 0.63, p = .006). No significant differences on treatment effects were observed between HT and the reference group I-TAU in the HoNOSCA (d = 0.01, p = .96) or the HoNOSCA-SR (d = 0.11, p = .63). Overall, results indicate HT to be an effective alternative for children and adolescents with acute mental health disorders instead of hospitalization. Further evaluation with random group allocation and long-term follow-up should attempt to replicate and extend the current findings.

Introducing a Group Therapy Program (PLAN D) for Young Outpatients with Derealization and Depersonalization: A Pilot Study.

Depersonalization and derealization (DD) cause significant distress and are associated with poor role and social functional outcomes. Despite the relatively high prevalence of DD symptoms and the chronic course in those suffering from a DD disorder, there still exists a need for effective interventions. Preliminary evidence indicates that cognitive behavioral therapy (CBT) delivered in an individual setting demonstrates some positive intervention effects for patients with DD regarding their symptom levels. By considering DD-specific treatment needs, a group therapy program was developed as an add-on therapy based on CBT techniques called PLAN D comprising the following elements: psychoeducation, lifestyle interventions, acceptance and mindfulness training, and new patterns of DD-related cognitions. In a pilot study, we present an 8-week group intervention for adolescents and young adults with DD disorder. To our knowledge, no standardized group intervention program for DD exists so far. Thus, this novel intervention represents a promising opportunity to positively influence long-term outcomes and course of DD.

[Positive Psychotic Symptoms in Childhood and Adolescence]. / Positiv psychotische Symptome in Kindheit und Jugend.

In both classification systems, DSM-5 and ICD-11, the diagnostic criteria of schizophreniaspectrum disorders in minors are identical to those of adults. Nevertheless, recent studies have emphasized important differences in phenomenology and clinical impact of positive psychotic symptoms between children, adolescents and young adults. Among positive psychotic symptoms, hallucinations have a high prevalence in childhood, where they are often described as vivid, multisensory experiences, that mostly remit spontaneously. In children, these symptoms are not necessarily associated with the emergence of schizophrenia-spectrum disorders. However, they can indicate comorbid psychiatric disorders and cause significant stress or, in other cases, be transient symptoms without any significant pathological value. The article provides a review on recent epidemiological and phenomenological findings on positive psychotic symptoms in children and adolescents and proposes diagnostic and therapeutic strategies on the management of these symptoms in minors.

Basic symptoms and gray matter volumes of patients at clinical high risk for psychosis.

BACKGROUND: Clinical high-risk (CHR) for psychosis is indicated by ultra-high risk (UHR) and basic symptom (BS) criteria; however, conversion rates are highest when both UHR and BS criteria are fulfilled (UHR&BS). While BSs are considered the most immediate expression of neurobiological aberrations underlying the development of psychosis, research on neurobiological correlates of BS is scarce. METHODS: We investigated gray matter volumes (GMV) of 20 regions of interest (ROI) previously associated with UHR criteria in 90 patients from the Bern early detection service: clinical controls (CC), first-episode psychosis (FEP), UHR, BS and UHR&BS. We expected lowest GMV in FEP and UHR&BS, and highest volume in CC with UHR and BS in-between. RESULTS: Significantly, lower GMV was detected in FEP and UHR&BS patients relative to CC with no other significant between-group differences. When ROIs were analyzed separately, seven showed a significant group effect (FDR corrected), with five (inferior parietal, medial orbitofrontal, lateral occipital, middle temporal, precuneus) showing significantly lower GM volume in the FEP and/or UHR&BS groups than in the CC group (Bonferroni corrected). In the CHR group, only COGDIS scores correlated negatively with cortical volumes. CONCLUSIONS: This is the first study to demonstrate that patients who fulfill both UHR and BS criteria - a population that has been associated with higher conversion rates - exhibit more severe GMV reductions relative to those who satisfy BS or UHR criteria alone. This result was mediated by the BS in the UHR&BS group, as only the severity of BS was linked to GMV reductions.

Dysregulation of kynurenine metabolism is related to proinflammatory cytokines, attention, and prefrontal cortex volume in schizophrenia.

The kynurenine pathway (KP) of tryptophan (TRP) catabolism links immune system activation with neurotransmitter signaling. The KP metabolite kynurenic acid (KYNA) is increased in the brains of people with schizophrenia. We tested the extent to which: (1) brain KP enzyme mRNAs, (2) brain KP metabolites, and (3) plasma KP metabolites differed on the basis of elevated cytokines in schizophrenia vs. control groups and the extent to which plasma KP metabolites were associated with cognition and brain volume in patients displaying elevated peripheral cytokines. KP enzyme mRNAs and metabolites were assayed in two independent postmortem brain samples from a total of 71 patients with schizophrenia and 72 controls. Plasma KP metabolites, cognition, and brain volumes were measured in an independent cohort of 96 patients with schizophrenia and 81 healthy controls. Groups were stratified based on elevated vs. normal proinflammatory cytokine mRNA levels. In the prefrontal cortex (PFC), kynurenine (KYN)/TRP ratio, KYNA levels, and mRNA for enzymes, tryptophan dioxygenase (TDO) and kynurenine aminotransferases (KATI/II), were significantly increased in the high cytokine schizophrenia subgroup. KAT mRNAs significantly correlated with mRNA for glial fibrillary acidic protein in patients. In plasma, the high cytokine schizophrenia subgroup displayed an elevated KYN/TRP ratio, which correlated inversely with attention and dorsolateral prefrontal cortex (DLPFC) volume. This study provides further evidence for the role of inflammation in a subgroup of patients with schizophrenia and suggests a molecular mechanism through which inflammation could lead to schizophrenia. Proinflammatory cytokines may elicit conversion of TRP to KYN in the periphery and increase the N-methyl-D-aspartate receptor antagonist KYNA via increased KAT mRNA and possibly more enzyme synthesis activity in brain astrocytes,  leading to DLPFC volume loss, and attention impairment in schizophrenia.

Age effects on basic symptoms in the community: A route to gain new insight into the neurodevelopment of psychosis?

Reports of limited clinical significance of attenuated psychotic symptoms before age 15/16 indicate an important role of neurodevelopment in the early detection of psychoses. Therefore, we examined if age also exerts an influence on the prevalence and clinical significance of the 14 cognitive and perceptive basic symptoms (BS) used in psychosis-risk criteria and conceptualized as the most direct self-experienced expression of neurobiological aberrations. A random representative general population sample of the Swiss canton Bern (N = 689, age 8-40 years, 06/2011-05/2014) was interviewed for BS, psychosocial functioning, and current mental disorder. BS were reported by 18% of participants, mainly cognitive BS (15%). In regression analyses, age affected perceptive and cognitive BS differently, indicating an age threshold for perceptive BS in late adolescence (around age 18) and for cognitive BS in young adulthood (early twenties)-with higher prevalence, but a lesser association with functional deficits and the presence of mental disorder in the below-threshold groups. Thereby, interaction effects between age and BS on functioning and mental disorder were commonly stronger than individual effects of age and BS. Indicating support of the proposed "substrate-closeness" of BS, differential age effects of perceptual and cognitive BS seem to follow normal brain maturation processes, in which they might occur as infrequent and temporary non-pathological disturbances. Their persistence or occurrence after conclusion of main brain maturation processes, however, might signify aberrant maturation or neurodegenerative processes. Thus, BS might provide important insight into the pathogenesis of psychosis and into differential neuroprotective or anti-inflammatory targets.

Disturbances of Agency and Ownership in Schizophrenia: An Auditory Verbal Event Related Potentials Study.

A 'sense of self' is essentially the ability to distinguish between self-generated and external stimuli. It consists of at least two very basic senses: a sense of agency and a sense of ownership. Disturbances seem to provide a basic deficit in many psychiatric diseases. The aim of our study was to manipulate those qualities separately in 28 patients with schizophrenia (14 auditory hallucinators and 14 non-hallucinators) and 28 healthy controls (HC) and to investigate the effects on the topographies and the power of the event-related potential (ERP). We performed a 76-channel EEG while the participants performed the task as in our previous paper. We computed ERPs and difference maps for the conditions and compared the amount of agency and ownership between the HC and the patients. Furthermore, we compared the global field power and the topographies of these effects. Our data showed effects of agency and ownership in the healthy controls and the hallucinator group and to a lesser degree in the non-hallucinator group. We found a reduction of the N100 during the presence of agency, and a bilateral temporal negativity related to the presence of ownership. For the agency effects, we found significant differences between HC and the patients. Contrary to the expectations, our findings were more pronounced in non-hallucinators, suggesting a more profoundly disturbed sense of agency compared to hallucinators. A contemporary increase of global field power in both patient groups indicates a compensatory recruitment of other mechanisms not normally associated with the processing of agency and ownership.

Agency and ownership are independent components of 'sensing the self' in the auditory-verbal domain.

'Sensing the self' relies on the ability to distinguish self-generated from external stimuli. It requires functioning mechanisms to establish feelings of agency and ownership. Agency is defined causally, where the subjects action is followed by an effect. Ownership is defined by the features of the effect, independent from the action. In our study, we manipulated these qualities separately. 13 right-handed healthy individuals performed the experiment while 76-channel EEG was recorded. Stimuli consisted of visually presented words, read aloud by the subject. The experiment consisted of six conditions: (a) subjects saw a word, read it aloud, heard it in their own voice; (b) like a, but the word was heard in an unfamiliar voice; (c) subject heard a word in his/her own voice without speaking; (d) like c, but the word was heard in an unfamiliar voice; (e) like a, but subjects heard the word with a delay; (f) subjects read without hearing. ERPs and difference maps were computed for all conditions. Effects were analysed topographically. The N100 (86-172 ms) displayed significant main effects of agency and ownership. The topographies of the two effects shared little common variance, suggesting independent effects. Later effects (174-400 ms) of agency and ownership were topographically similar, suggesting common mechanisms. Replicating earlier studies, significant N100 suppression was observed, with a topography resembling the agency effect. 'Sensing the self' appears to recruit from at least two very distinct processes: an agency assessment that represents causality and an ownership assessment that compares stimulus features with memory content.

Reduced anterior callosal white matter in risk for psychosis associated with processing speed as a fundamental cognitive impairment.

BACKGROUND: Previous research in psychotic disorders discovered associations between reduced integrity of white matter (WM) in the corpus callosum (CC) and impaired cognitive functions, suggesting processing speed as a central construct. However, it is still largely unexplored to what extent disruption in callosal WM is related to cognitive deficits during the risk stage prior to psychosis. METHODS: To address this gap, we measured the WM integrity in CC by fractional anisotropy (FA) and assessed cognition in 60 clinical-high risk for psychosis (CHR) patients during adolescence/young adulthood and 38 healthy control (HC) subjects. We employed tract based spatial statistics to examine group differences and associations between CC-FA and processing speed, executive function, and spatial working memory. RESULTS: We revealed deficits in processing speed, executive function, and spatial working memory of CHR patients, and reductions in FA of the genu and the body of the CC (p < 0.05, corrected for multiple comparisons) compared to HC. A mediation analysis using the combined sample (CHR + HC) showed that processing speed mediates the associations between the impaired CC structure and executive function and spatial working memory, respectively. Exploratory analyses between CC-FA and the cognitive domains located associations of processing speed in the genu and the body of CC with distinct spatial distributions of executive function and spatial working memory. CONCLUSION: We suggest processing speed as a subordinate cognitive factor contributing to the associations between callosal WM, executive function and working memory. These results extend findings in psychotic disorders to the prior risk stage.

Aberrant brain dynamics in individuals with clinical high risk of psychosis.

Background: Resting-state network (RSN) functional connectivity analyses have profoundly influenced our understanding of the pathophysiology of psychoses and their clinical high risk (CHR) states. However, conventional RSN analyses address the static nature of large-scale brain networks. In contrast, novel methodological approaches aim to assess the momentum state and temporal dynamics of brain network interactions. Methods: Fifty CHR individuals and 33 healthy controls (HC) completed a resting-state functional MRI scan. We performed an Energy Landscape analysis, a data-driven method using the pairwise maximum entropy model, to describe large-scale brain network dynamics such as duration and frequency of, and transition between, different brain states. We compared those measures between CHR and HC, and examined the association between neuropsychological measures and neural dynamics in CHR. Results: Our main finding is a significantly increased duration, frequency, and higher transition rates to an infrequent brain state with coactivation of the salience, limbic, default mode and somatomotor RSNs in CHR as compared to HC. Transition of brain dynamics from this brain state was significantly correlated with processing speed in CHR. Conclusion: In CHR, temporal brain dynamics are attracted to an infrequent brain state, reflecting more frequent and longer occurrence of aberrant interactions of default mode, salience, and limbic networks. Concurrently, more frequent and longer occurrence of the brain state is associated with core cognitive dysfunctions, predictors of future onset of full-blown psychosis.

EEG microstate D as psychosis-specific correlate in adolescents and young adults with clinical high risk for psychosis and first-episode psychosis.

Resting-state electroencephalography (EEG) microstates are brief periods (60-120 ms) of quasi-stable scalp field potentials, indicating simultaneous activity of large-scale networks. Microstates are assumed to reflect basic neuronal information processing. A common finding in psychosis spectrum disorders is that microstates classes C and D are altered. Whereas evidence in adults with schizophrenia is substantial, little is known about effects in underage patients, particularly in those at clinical high risk for psychosis (CHR) and first-episode psychosis (FEP). The present study used 74-channel EEG to investigate microstate effects in a large sample of patients with CHR (n = 100) and FEP (n = 33), clinical controls (CC, n = 18), as well as age-matched healthy controls (HC, n = 68). Subjects span an age range from 9 to 35 years, thus, covering underage patients as well as the most vulnerable period for the emergence of psychosis and its prodrome. Four EEG microstates classes were analyzed (A-D). In class D, CHR and FEP patients showed a decrease compared to HC, and CHR patients also to CC. An increase in class C was found in CHR and FEP compared to HC but not to CC. Results were independent of age and no differences were found between the psychosis spectrum groups. The findings suggest an age-independent decrease of microstate class D to be specific to the psychosis spectrum, whereas the increase in class C seems to reflect unspecific psychopathology. Overall, present data strengthens the role of microstate D as potential biomarker for psychosis, as early as in adolescence and already in CHR status.

Toll-Like Receptor mRNA Levels in Schizophrenia: Association With Complement Factors and Cingulate Gyrus Cortical Thinning.

BACKGROUND AND HYPOTHESES: Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. STUDY DESIGN: Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. STUDY RESULTS: We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. CONCLUSIONS: The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.

Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis.

Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (ß = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (ß = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.

Exploring the complex relationships between coping strategies, locus of control and self-esteem with psychopathology: structural equation modeling with a special focus on clinical high-risk of psychosis.

BACKGROUND: Coping strategies, competence, and locus of control (LOC) beliefs are important predictors of mental health (MH). However, research into their complex interactions has produced mixed results. Our study investigated them further in the previously unexplored context of clinical high-risk (CHR) of psychosis. METHODS: We tested six alternative structural equation models in a community sample (N = 523), hypothesizing a mediating role of coping and treating CHR symptoms as (i) an additional mediator or (ii) a specific outcome. Our measurement model included two latent factors of MH: (1) psychopathology (PP), consisting of presence of mental disorders, global and psychosocial functioning, and (2) self-rated health (SRH) status. RESULTS: In the model with the best Akaike Information Criterion and the latent factors as outcome variables, maladaptive coping completely mediated the impact of maladaptive LOC on PP and SRH. Additionally, CHR symptoms partially mediated the effect of maladaptive coping on PP and SRH in the community sample, as long as sex was not entered into the model. In the clinical sample (N = 371), the model did not support a mediation by CHR symptoms, despite significant pathways with both coping and MH outcomes; further, competence beliefs directly impacted SRH. CONCLUSIONS: Coping strategies are an important intervention target for MH promotion, especially in the community. In clinical populations, interventions focusing on coping strategies may improve CHR symptoms, thus potentially supporting better MH, especially SRH. Additionally, due to their mostly cascading effects on MH, improving competence and LOC beliefs may also promote psychological well-being.

Case report: Psychosis and catatonia in an adolescent patient with adipsic hypernatremia and autoantibodies against the subfornical organ.

This is the first description of a patient in which adipsic hypernatremia, a rare autoimmune encephalitis, presented in combination with complex psychiatric symptomatology, including psychosis and catatonia. Adipsic hypernatremia is characterized by autoantibodies against the thirst center of the brain. These autoantibodies cause inflammation and apoptosis in key regions of water homeostasis, leading to lack of thirst and highly increased serum sodium. To date, the symptoms of weakness, fatigue and drowsiness have been associated with adipsic hypernatremia, but no psychiatric symptomatology. Here, we showcase the first description of an adolescent patient, in which severe and complex psychiatric symptoms presented along with adipsic hypernatremia. The patient experienced delusion, hallucinations, restlessness and pronounced depression. Further, he showed ritualized, aggressive, disinhibited and sexualized behavior, as well as self-harm and psychomotor symptoms. Due to his severe condition, he was hospitalized on the emergency unit of the child and adolescent psychiatry for 8 months. Key symptoms of the presented clinical picture are: childhood-onset complex and treatment-resistant psychosis/catatonia, pronounced behavioral problems, fatigue, absent thirst perception, hypernatremia and elevated prolactin levels. This case report renders first evidence speaking for a causal link between the autoimmune adipsic hypernatremia and the psychotic disorder. Moreover, it sheds light on a new form of autoimmune psychosis.