Matrix metalloproteinase 9 (MMP-9) activity, hippocampal extracellular free water, and cognitive deficits are associated with each other in early phase psychosis.

Increasing evidence points toward the role of the extracellular matrix, specifically matrix metalloproteinase 9 (MMP-9), in the pathophysiology of psychosis. MMP-9 is a critical regulator of the crosstalk between peripheral and central inflammation, extracellular matrix remodeling, hippocampal development, synaptic pruning, and neuroplasticity. Here, we aim to characterize the relationship between plasma MMP-9 activity, hippocampal microstructure, and cognition in healthy individuals and individuals with early phase psychosis. We collected clinical, blood, and structural and diffusion-weighted magnetic resonance imaging data from 39 individuals with early phase psychosis and 44 age and sex-matched healthy individuals. We measured MMP-9 plasma activity, hippocampal extracellular free water (FW) levels, and hippocampal volumes. We used regression analyses to compare MMP-9 activity, hippocampal FW, and volumes between groups. We then examined associations between MMP-9 activity, FW levels, hippocampal volumes, and cognitive performance assessed with the MATRICS battery. All analyses were controlled for age, sex, body mass index, cigarette smoking, and years of education. Individuals with early phase psychosis demonstrated higher MMP-9 activity (p < 0.0002), higher left (p < 0.05) and right (p < 0.05) hippocampal FW levels, and lower left (p < 0.05) and right (p < 0.05) hippocampal volume than healthy individuals. MMP-9 activity correlated positively with hippocampal FW levels (all participants and individuals with early phase psychosis) and negatively with hippocampal volumes (all participants and healthy individuals). Higher MMP-9 activity and higher hippocampal FW levels were associated with slower processing speed and worse working memory performance in all participants. Our findings show an association between MMP-9 activity and hippocampal microstructural alterations in psychosis and an association between MMP-9 activity and cognitive performance. Further, more extensive longitudinal studies should examine the therapeutic potential of MMP-9 modulators in psychosis.

Associations between antipsychotics-induced weight gain and brain networks of impulsivity.

Given the unpredictable rapid onset and ubiquitous consequences of weight gain induced by antipsychotics, there is a pressing need to get insights into the underlying processes at the brain system level that will allow stratification of "at risk" patients. The pathophysiological hypothesis at hand is focused on brain networks governing impulsivity that are modulated by neuro-inflammatory processes. To this aim, we investigated brain anatomy and functional connectivity in patients with early psychosis (median age: 23 years, IQR = 21-27) using anthropometric data and magnetic resonance imaging acquired one month to one year after initiation of AP medication. Our analyses included 19 patients with high and rapid weight gain (i.e., ≥5% from baseline weight after one month) and 23 patients with low weight gain (i.e., <5% from baseline weight after one month). We replicated our analyses in young (26 years, IQR = 22-33, N = 102) and middle-aged (56 years, IQR = 51-62, N = 875) healthy individuals from the general population. In early psychosis patients, higher weight gain was associated with poor impulse control score (ß = 1.35; P = 0.03). Here, the observed brain differences comprised nodes of impulsivity networks - reduced frontal lobe grey matter volume (Pcorrected = 0.007) and higher striatal volume (Pcorrected = 0.048) paralleled by disruption of fronto-striatal functional connectivity (R = -0.32; P = 0.04). Weight gain was associated with the inflammatory biomarker plasminogen activator inhibitor-1 (ß = 4.9, P = 0.002). There was no significant association between increased BMI or weight gain and brain anatomy characteristics in both cohorts of young and middle-aged healthy individuals. Our findings support the notion of weight gain in treated psychotic patients associated with poor impulse control, impulsivity-related brain networks and chronic inflammation.

Sex-specific interactions between stress axis and redox balance are associated with internalizing symptoms and brain white matter microstructure in adolescents.

Adolescence is marked by the maturation of systems involved in emotional regulation and by an increased risk for internalizing disorders (anxiety/depression), especially in females. Hypothalamic-pituitary-adrenal (HPA)-axis function and redox homeostasis (balance between reactive oxygen species and antioxidants) have both been associated with internalizing disorders and may represent critical factors for the development of brain networks of emotional regulation. However, sex-specific interactions between these factors and internalizing symptoms and their link with brain maturation remain unexplored. We investigated in a cohort of adolescents aged 13-15 from the general population (n = 69) whether sex-differences in internalizing symptoms were associated with the glutathione (GSH)-redox cycle homeostasis and HPA-axis function and if these parameters were associated with brain white matter microstructure development. Female adolescents displayed higher levels of internalizing symptoms, GSH-peroxidase (GPx) activity and cortisol/11-deoxycortisol ratio than males. There was a strong correlation between GPx and GSH-reductase (Gred) activities in females only. The cortisol/11-deoxycortisol ratio, related to the HPA-axis activity, was associated with internalizing symptoms in both sexes, whereas GPx activity was associated with internalizing symptoms in females specifically. The cortisol/11-deoxycortisol ratio mediated sex-differences in internalizing symptoms and the association between anxiety and GPx activity in females specifically. In females, GPx activity was positively associated with generalized fractional anisotropy in widespread white matter brain regions. We found that higher levels of internalizing symptoms in female adolescents than in males relate to sex-differences in HPA-axis function. In females, our results suggest an important interplay between HPA-axis function and GSH-homeostasis, a parameter strongly associated with brain white matter microstructure.

Covalent Proteins as Targeted Radionuclide Therapies Enhance Antitumor Effects.

Molecularly targeted radionuclide therapies (TRTs) struggle with balancing efficacy and safety, as current strategies to increase tumor absorption often alter drug pharmacokinetics to prolong circulation and normal tissue irradiation. Here we report the first covalent protein TRT, which, through reacting with the target irreversibly, increases radioactive dose to the tumor without altering the drug's pharmacokinetic profile or normal tissue biodistribution. Through genetic code expansion, we engineered a latent bioreactive amino acid into a nanobody, which binds to its target protein and forms a covalent linkage via the proximity-enabled reactivity, cross-linking the target irreversibly in vitro, on cancer cells, and on tumors in vivo. The radiolabeled covalent nanobody markedly increases radioisotope levels in tumors and extends tumor residence time while maintaining rapid systemic clearance. Furthermore, the covalent nanobody conjugated to the α-emitter actinium-225 inhibits tumor growth more effectively than the noncovalent nanobody without causing tissue toxicity. Shifting the protein-based TRT from noncovalent to covalent mode, this chemical strategy improves tumor responses to TRTs and can be readily scaled to diverse protein radiopharmaceuticals engaging broad tumor targets.

The proximity-enabled sulfur fluoride exchange reaction in the protein context.

The proximity-enabled sulfur(vi) fluoride exchange (SuFEx) reaction generates specific covalent linkages between proteins in cells and in vivo, which opens innovative avenues for studying elusive protein-protein interactions and developing potent covalent protein drugs. To exploit the power and expand the applications of covalent proteins, covalent linkage formation between proteins is the critical step, for which fundamental kinetic and essential properties remain unexplored. Herein, we systematically studied SuFEx kinetics in different proteins and conditions. In contrast to in small molecules, SuFEx in interacting proteins conformed with a two-step mechanism involving noncovalent binding, followed by covalent bond formation, exhibiting nonlinear rate dependence on protein concentration. The protein SuFEx rate consistently changed with protein binding affinity as well as chemical reactivity of the functional group and was impacted by target residue identity and solution pH. In addition, kinetic analyses of nanobody SR4 binding with SARS-CoV-2 spike protein revealed that viral target mutations did not abolish covalent binding but decreased the SuFEx rate with affinity decrease. Moreover, off-target cross-linking of a SuFEx-capable nanobody in human serum was not detected, and the SuFEx-generated protein linkage was stable at cellular acidic pHs, suggesting SuFEx suitability for in vivo usage. These results advanced our understanding of SuFEx reactivity and kinetics in proteins, which is invaluable for ongoing exploration of SuFEx-enabled covalent proteins for basic biological research and creative biotherapeutics.

Case report: Treatment-resistant depression, multiple trauma exposure and suicidality in an adolescent female with previously undiagnosed Autism Spectrum Disorder.

High rates of co-occurring depression are commonly reported in youth with Autism Spectrum Disorder (ASD), especially in individuals without intellectual disability (ID). Depression in ASD undermines adaptive behavior and is associated with a higher risk of suicidality. Females with ASD may be particularly vulnerable due to their greater use of camouflaging strategies. Indeed, in comparison to males, ASD is underdiagnosed in females, despite higher rates of internalizing symptoms and suicidality. Trauma exposure may also play a role in the development of depressive symptoms in this population. Moreover, evidence for effective treatments of depression in autistic youth are lacking, with ASD individuals frequently experiencing low efficacy and side effects. We present the case of an adolescent female with previously undiagnosed ASD without ID, admitted for active suicidal plans and a treatment-resistant depression (TRD), occurred after a COVID-19 lockdown in the context of cumulative exposure to stressful life events. Comprehensive clinical assessments performed at intake confirmed severe depression with suicidality. Intensive psychotherapy and different changes in medications were carried out (SSRI, SNRI, SNRI + NaSSA, SNRI + aripiprazole), all of which were ineffective, with persistent suicidal thoughts, often requiring intensive individual monitoring. The patient was finally successfully treated with lithium augmentation of fluoxetine, with no side effects. During hospitalization she was also evaluated by an ASD specialized center, where a diagnosis of ASD was made according to the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview-Revised (ADI-R) scores, as well as to clinical judgment of a senior psychiatrist. The present case report shows that clinicians should not overlook undiagnosed autism as a possible cause of TRD, especially in females without ID, where higher rates of under diagnosis may be in part related to their greater use of camouflage. It also suggests that ASD underdiagnosis and resulting unmet needs may be involved in vulnerability to stressful experiences, depression, and suicidality. Furthermore, it shows the complexity of providing care to TRD in youth with autism, suggesting that an augmentation therapy with lithium, a commonly recommended therapeutic strategy for refractory depression in typically developing samples, may also be effective in this population.

Characterization of early psychosis patients carrying a genetic vulnerability to redox dysregulation: a computational analysis of mechanism-based gene expression profile in fibroblasts.

In view of its heterogeneity, schizophrenia needs new diagnostic tools based on mechanistic biomarkers that would allow early detection. Complex interaction between genetic and environmental risk factors may lead to NMDAR hypofunction, inflammation and redox dysregulation, all converging on oxidative stress. Using computational analysis, the expression of 76 genes linked to these systems, known to be abnormally regulated in schizophrenia, was studied in skin-fibroblasts from early psychosis patients and age-matched controls (N = 30), under additional pro-oxidant challenge to mimic environmental stress. To evaluate the contribution of a genetic risk related to redox dysregulation, we investigated the GAG trinucleotide polymorphism in the key glutathione (GSH) synthesizing enzyme, glutamate-cysteine-ligase-catalytic-subunit (gclc) gene, known to be associated with the disease. Patients and controls showed different gene expression profiles that were modulated by GAG-gclc genotypes in combination with oxidative challenge. In GAG-gclc low-risk genotype patients, a global gene expression dysregulation was observed, especially in the antioxidant system, potentially induced by other risks. Both controls and patients with GAG-gclc high-risk genotype (gclcGAG-HR) showed similar gene expression profiles. However, under oxidative challenge, a boosting of other antioxidant defense, including the master regulator Nrf2 and TRX systems was observed only in gclcGAG-HR controls, suggesting a protective compensation against the genetic GSH dysregulation. Moreover, RAGE (redox/inflammation interaction) and AGMAT (arginine pathway) were increased in the gclcGAG-HR patients, suggesting some additional risk factors interacting with this genotype. Finally, the use of a machine-learning approach allowed discriminating patients and controls with an accuracy up to 100%, paving the way towards early detection of schizophrenia.

Perceived impact of the COVID-19 pandemic on child and adolescent psychiatric services after 1 year (February/March 2021): ESCAP CovCAP survey.

In April 2020, the European Society for Child and Adolescent Psychiatry (ESCAP) Research Academy and the ESCAP Board launched the first questionnaire of the CovCAP longitudinal survey to estimate the impact of COVID-19 on child and adolescent psychiatry (CAP) services in Europe. In this brief report, we present the main findings from the second questionnaire of the survey, one year after the COVID-19 pandemic began to hit Europe (i.e., February/March 2021). While service delivery to patients and their families was affected in a major way (reported by 68%) at the beginning of the pandemic, the majority of respondents (59%) in this second survey only reported a minor impact on care delivery. The use of telemedicine remained widespread (91%) but the proportion of CAP services partially closed or transformed to accommodate COVID-19 patients (59% in 2020) dropped to 20%. On the other hand, the perceived impact on the mental health and psychopathology of children and adolescents dramatically increased from "medium" (> 50%) in 2020 to "strong" or "extreme" (80%) in 2021. Four nosographic entities were particularly impacted: suicidal crises, anxiety disorders, eating disorders and major depressive episodes. Accordingly, this was associated with a substantial increase in the number of referrals or requests for assessments (91% reported an increase in 2021 while 61% reported a decrease in 2020). Finally, heads of the CAP departments expressed strong concerns regarding the management of the long-term consequences of this crisis, especially regarding the provision of care in light of the perceived increase in referrals.

Multimodal Magnetic Resonance Imaging Depicts Widespread and Subregion Specific Anomalies in the Thalamus of Early-Psychosis and Chronic Schizophrenia Patients.

BACKGROUND AND HYPOTHESIS: Although the thalamus has a central role in schizophrenia pathophysiology, contributing to sensory, cognitive, and sleep alterations, the nature and dynamics of the alterations occurring within this structure remain largely elusive. Using a multimodal magnetic resonance imaging (MRI) approach, we examined whether anomalies: (1) differ across thalamic subregions/nuclei, (2) are already present in the early phase of psychosis (EP), and (3) worsen in chronic schizophrenia (SCHZ). STUDY DESIGN: T1-weighted and diffusion-weighted images were analyzed to estimate gray matter concentration (GMC) and microstructural parameters obtained from the spherical mean technique (intra-neurite volume fraction [VFINTRA)], intra-neurite diffusivity [DIFFINTRA], extra-neurite mean diffusivity [MDEXTRA], extra-neurite transversal diffusivity [TDEXTRA]) within 7 thalamic subregions. RESULTS: Compared to age-matched controls, the thalamus of EP patients displays previously unreported widespread microstructural alterations (VFINTRA decrease, TDEXTRA increase) that are associated with similar alterations in the whole brain white matter, suggesting altered integrity of white matter fiber tracts in the thalamus. In both patient groups, we also observed more localized and heterogenous changes (either GMC decrease, MDEXTRA increase, or DIFFINTRA decrease) in mediodorsal, posterior, and ventral anterior parts of the thalamus in both patient groups, suggesting that the nature of the alterations varies across subregions. GMC and DIFFINTRA in the whole thalamus correlate with global functioning, while DIFFINTRA in the subregion encompassing the medial pulvinar is significantly associated with negative symptoms in SCHZ. CONCLUSION: Our data reveals both widespread and more localized thalamic anomalies that are already present in the early phase of psychosis.

Encoding latent SuFEx reactive meta-fluorosulfate tyrosine to expand covalent bonding of proteins.

The introduction of new covalent bonds into proteins is affording novel avenues for protein research and applications, yet it remains difficult to generate covalent linkages at all possible sites and across diverse protein classes. Herein, we genetically encoded meta-fluorosulfate-L-tyrosine (mFSY) to selectively react with lysine, tyrosine, and histidine via proximity-enabled SuFEx reaction. mFSY was able to target residues that were elusive for previous unnatural amino acids, and permitted engineering of various proteins including affibody, nanobody, and Fab into covalent binders that irreversibly cross-linked EGFR and HER2. mFSY is thus valuable for developing covalent proteins for biological research, synthetic biology, and biotherapeutics.

Caught in vicious circles: a perspective on dynamic feed-forward loops driving oxidative stress in schizophrenia.

A growing body of evidence has emerged demonstrating a pathological link between oxidative stress and schizophrenia. This evidence identifies oxidative stress as a convergence point or "central hub" for schizophrenia genetic and environmental risk factors. Here we review the existing experimental and translational research pinpointing the complex dynamics of oxidative stress mechanisms and their modulation in relation to schizophrenia pathophysiology. We focus on evidence supporting the crucial role of either redox dysregulation, N-methyl-D-aspartate receptor hypofunction, neuroinflammation or mitochondria bioenergetics dysfunction, initiating "vicious circles" centered on oxidative stress during neurodevelopment. These processes would amplify one another in positive feed-forward loops, leading to persistent impairments of the maturation and function of local parvalbumin-GABAergic neurons microcircuits and myelinated fibers of long-range macrocircuitry. This is at the basis of neural circuit synchronization impairments and cognitive, emotional, social and sensory deficits characteristic of schizophrenia. Potential therapeutic approaches that aim at breaking these different vicious circles represent promising strategies for timely and safe interventions. In order to improve early detection and increase the signal-to-noise ratio for adjunctive trials of antioxidant, anti-inflammatory and NMDAR modulator drugs, a reverse translation of validated circuitry approach is needed. The above presented processes allow to identify mechanism based biomarkers guiding stratification of homogenous patients groups and target engagement required for successful clinical trials, paving the way towards precision medicine in psychiatry.

Randomized controlled trial of a mindfulness-based intervention in adolescents from the general population: The Mindfulteen neuroimaging study protocol.

AIM: Adolescence is a period of vulnerability to stress. Increased anxiety during this period has been associated with the later development of mental disorders, hence the growing interest for interventions that could decrease stress reactivity and improve cognitive control in adolescents. Mindfulness-based interventions have demonstrated their efficacy on stress reactivity and anxiety in adults, but evidence is lacking in youth. METHODS: The Mindfulteen Study is a 3-year longitudinal cohort with a nested randomized controlled trial examining the effectiveness of mindfulness-based interventions for adolescents. Young adolescents from the general population, aged between 13 and 15 years old, with no history of current mental health disorder (apart from past mood disorders or current anxiety disorders) are included and stratified into low or high anxiety based on trait anxiety scores before being randomized to early or late 8-week intervention groups. Primary outcomes are based on neuroimaging data (i.e., structural and functional measures in the cortico-limbic network) while secondary outcomes are psychological (i.e., anxiety and stress-associated dimensions) and biological (i.e., cortisol, inflammatory and redox markers). Assessments are performed at baseline, immediately after intervention or waiting time and after 18 months of intervention. CONCLUSION: To the best of our knowledge, this is the first randomized controlled trail examining the effect of a mindfulness-based intervention in young adolescents from the general population based on the measurement and analyses of psychological, neuroimaging and biological data.

Mitochondrial, exosomal miR137-COX6A2 and gamma synchrony as biomarkers of parvalbumin interneurons, psychopathology, and neurocognition in schizophrenia.

Early detection and intervention in schizophrenia requires mechanism-based biomarkers that capture neural circuitry dysfunction, allowing better patient stratification, monitoring of disease progression and treatment. In prefrontal cortex and blood of redox dysregulated mice (Gclm-KO ± GBR), oxidative stress induces miR-137 upregulation, leading to decreased COX6A2 and mitophagy markers (NIX, Fundc1, and LC3B) and to accumulation of damaged mitochondria, further exacerbating oxidative stress and parvalbumin interneurons (PVI) impairment. MitoQ, a mitochondria-targeted antioxidant, rescued all these processes. Translating to early psychosis patients (EPP), blood exosomal miR-137 increases and COX6A2 decreases, combined with mitophagy markers alterations, suggest that observations made centrally and peripherally in animal model were reflected in patients' blood. Higher exosomal miR-137 and lower COX6A2 levels were associated with a reduction of ASSR gamma oscillations in EEG. As ASSR requires proper PVI-related networks, alterations in miR-137/COX6A2 plasma exosome levels may represent a proxy marker of PVI cortical microcircuit impairment. EPP can be stratified in two subgroups: (a) a patients' group with mitochondrial dysfunction "Psy-D", having high miR-137 and low COX6A2 levels in exosomes, and (b) a "Psy-ND" subgroup with no/low mitochondrial impairment, including patients having miR-137 and COX6A2 levels in the range of controls. Psy-D patients exhibited more impaired ASSR responses in association with worse psychopathological status, neurocognitive performance, and global and social functioning, suggesting that impairment of PVI mitochondria leads to more severe disease profiles. This stratification would allow, with high selectivity and specificity, the selection of patients for treatments targeting brain mitochondria dysregulation and capture the clinical and functional efficacy of future clinical trials.

ESCAP CovCAP survey of heads of academic departments to assess the perceived initial (April/May 2020) impact of the COVID-19 pandemic on child and adolescent psychiatry services.

In April 2020, the European Society for Child and Adolescent Psychiatry (ESCAP) Research Academy and the ESCAP Board launched the first of three scheduled surveys to evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on child and adolescent psychiatry (CAP) services in Europe and to assess the abilities of CAP centers to meet the new challenges brought on by the crisis. The survey was a self-report questionnaire, using a multistage process, which was sent to 168 heads of academic CAP services in 24 European countries. Eighty-two responses (56 complete) from 20 countries, representing the subjective judgement of heads of CAP centers, were received between mid-April and mid-May 2020. Most respondents judged the impact of the crisis on the mental health of their patients as medium (52%) or strong (33%). A large majority of CAP services reported no COVID-19 positive cases among their inpatients and most respondents declared no or limited sick leaves in their team due to COVID-19. Outpatient, daycare, and inpatient units experienced closures or reductions in the number of treated patients throughout Europe. In addition, a lower referral rate was observed in most countries. Respondents considered that they were well equipped to handle COVID-19 patients despite a lack of protective equipment. Telemedicine was adopted by almost every team despite its sparse use prior to the crisis. Overall, these first results were surprisingly homogeneous, showing a substantially reduced patient load and a moderate effect of the COVID-19 crisis on psychopathology. The effect on the organization of CAP services appears profound. COVID-19 crisis has accelerated the adoption of new technologies, including telepsychiatry.