The relationship between oxidative stress and psychotic disorders in 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 Deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. This condition is associated with a wide range of symptoms including immune and neuropsychiatric disorders. Notably, psychotic disorders including schizophrenia have a prevalence of âˆ¼ 30%. A growing body of evidence indicates that neuroinflammation and oxidative stress (OS) play a role in the pathophysiology of schizophrenia. In this study, we aim to assess the interaction between 22q11.2DS, OS and schizophrenia. METHODS: Blood samples were collected from 125 participants (including individuals with 22q11.2DS [n = 73] and healthy controls [n = 52]) from two sites: Sheba Medical Center in Israel, and University Hospital Gasthuisberg in Belgium. Baseline OS levels were evaluated by measuring Myeloperoxidase (MPO) activity. A sub-sample of the Israeli sample (n = 50) was further analyzed to examine survival of Peripheral Blood Mononuclear Cells (PBMCs) following induction of OS using vitamin K3. RESULTS: The levels of MPO were significantly higher in all individuals with 22q11.2DS, compared to healthy controls (0.346 ± 0.256 vs. 0.252 ± 0.238, p =.004). In addition, when comparing to healthy controls, the PBMCs of individuals with 22q11.2DS were less resilient to induced OS, specifically the group diagnosed with psychotic disorder (0.233 ± 0.206 for the 22q11.2DS individuals with psychotic disorders, 0.678 ± 1.162 for the 22q11.2DS individuals without psychotic disorders, and 1.428 ± 1.359 for the healthy controls, p =.003, η2 = 0.207). CONCLUSIONS: Our results suggest that dysregulation of OS mechanisms may play a role in the pathophysiology of the 22q11.2DS phenotype. The 22q11.2DS individuals with psychotic disorders were more sensitive to induction of OS, but did not present significantly different levels of OS at baseline. These results may be due to the effect of antipsychotic treatment administered to this sup-group. By elucidating novel molecular pathways, early identification of biochemical risk markers for 22q11.2DS and psychotic disorders can be detected. This can ultimately pave the way to the design of early and more precise interventions of individuals with 22q11.2DS.

A 16-month longitudinal investigation of risk and protective factors for mental health outcomes throughout three national lockdowns and a mass vaccination campaign: Evidence from a weighted Israeli sample during COVID-19.

BACKGROUND: COVID-19 is an ongoing global crisis, with a multitude of factors that affect mental health worldwide. We explored potential predictors for the emergence and maintenance of depression, anxiety, and posttraumatic stress symptoms (PTSS) in the general population in Israel. METHODS: Across the span of 16 months, 2478 people completed a repeated self-report survey which inquired psychiatric symptoms and pandemic related stress factors (PRSF). We applied mixed-effects models to assess how each stressor contributes to depression, anxiety and PTSS at each time point, and longitudinally assessed participants who completed at least two consecutive surveys (n = 400). We weighted our sample to increase representativeness of the population. RESULTS: Fatigue was the strongest predictor for depression, anxiety and PTSS at all time points, and predicted deterioration overtime. Financial concerns associated with depression and anxiety at all time points, and with their deterioration overtime. Health related concerns were uniquely associated with anxiety and PTSS at all time points and their deterioration, but not with depression. Improvement in sense of protection overtime associated with decrease in depression and anxiety. Hesitancy towards vaccination was associated to higher financial concerns and lower sense of protection by the authorities. CONCLUSIONS: Our findings accentuate the multitude of risk factors for psychiatric morbidity during COVID-19, and the centrality of fatigue in determining mental health outcomes.

Child and Adolescent Mental Health during the COVID-19 Pandemic: Challenges of Psychiatric Outpatient Clinics.

BACKGROUND: Worldwide national surveys show a rising mental health burden among children and adolescents (C&A) during COVID-19. The objective of the current study is to verify the expected rise in visits to psychiatric outpatient clinics of C&A, especially of new patients. METHODS: a cross-sectional study focusing on visits as recorded in electronic medical records of eight heterogeneous C&A psychiatric outpatient clinics. The assessment was based on visits held from March to December of 2019 (before the pandemic) in comparison to visits held in 2020 (during the pandemic). RESULTS: The number of visits was similar for both periods. However, in 2020, 17% of the visits used telepsychiatry (N = 9885). Excluding telepsychiatry reveals a monthly decrease in traditional in-person activities between 2020 and 2019 (691.6 ± 370.8 in 2020 vs. 809.1 ± 422.8 in 2019, mean difference = -117.5, t (69) = -4.07, p = 0.0002, Cohen's d = -0.30). Acceptation of new patients declined during 2020, compared to 2019 (50.0 ± 38.2 in 2020 vs. 62.8 ± 42.9 in 2019; Z = -3.12, p = 0.002, r = 0.44). Telepsychiatry was not used for new patients. CONCLUSIONS: The activity of C&A psychiatric outpatient clinics did not rise but was guarded due to the use of telepsychiatry. The decline in visits of new patients was explained by the lack of use of telepsychiatry for these patients. This calls for expanding the use of telepsychiatry, especially for new patients.

Internalizing symptoms impede adolescents' ability to transition from in-person to online mental health services during the 2019 coronavirus disease pandemic.

INTRODUCTION: Online mental health services were previously found to be effective in many studies. However, this method was not generally used in Israel. By the end of 2019, the coronavirus disease 2019 pandemic erupted, forcing mental health services to transition to online meetings to maintain the standard of care. In this cross-sectional study, we investigated the attitudes of adolescent patients toward this involuntary new mode of care. METHODS: Forty-four adolescents (mean age 14.62 ± 2.12 years, 54.5% females) and 40 of their primary caregivers completed a battery of questionnaires that included the telemedicine satisfaction questionnaire, session evaluation questionnaire, working alliance inventory, and pediatric symptom checklist. RESULTS: Both adolescents and their caregivers reported a reasonable experience with the online medium and a feeling that the meetings were overall powerful, helpful, and comfortable as demonstrated by medium to high scores on the telemedicine satisfaction questionnaire and session evaluation questionnaire questionnaires. A therapeutic alliance was generally maintained according to working alliance inventory scores. However, working alliance inventory scores were negatively correlated with higher levels of internalizing symptoms and parental stress. DISCUSSION: Our findings point to the possibility that anxious/depressed adolescents will have greater difficulties re-establishing therapeutic alliance when transitioned from in-person to online meetings. This may be due to the introduction of an "invisible" third party to the therapeutic setting-the computer. Psychologists and psychiatrists should be aware of these difficulties and respond adequately to maintain the standard of care.

Loneliness and Social Media Use Among Adolescents with Psychiatric Disorders.

Studies have demonstrated that a prolonged feeling of loneliness is a major risk factor for psychopathology among children and adolescents. The purpose of this study was to evaluate the association between patterns of social media use with loneliness and psychopathology among 65 adolescents who were diagnosed with psychiatric disorders and treated at a psychiatric outpatient clinic in Israel. Social capital (online and offline) was negatively associated with loneliness. There was no association between loneliness and patterns of social media use, age, gender, psychiatric diagnosis, or disease severity. Our findings indicate that both online and offline social capital are associated with loneliness, and highlight the importance of studying the effect of peer online social support in alleviating loneliness.

Keeping it simple: mental health assessment in the Gastroenterology Department - using the Hospital Anxiety and Depression Scale (HADS) for IBD patients in Israel.

BACKGROUND: Depression and anxiety are common among inflammatory bowel disease (IBD) patients. Not only do they worsen quality of life, but also worsen the prognosis of the IBD. Yet, there are no widely accepted guidelines for screening for depression or anxiety in this population. The Hospital Anxiety and Depression Scale (HADS) is a self-administered questionnaire designed to measure anxiety and depression in the physically ill. The purpose of this study was to establish the utility of the HADS as a screening tool in IBD patients. METHODS: Seventy-nine IBD patients (age 29.86 ± 8.36, 51.9% female, 77.2% Crohn's disease) were recruited consecutively at the day treatment unit, Gastroenterology Department, Sheba Medical Center. They were asked to complete the HADS, the Beck Depression Inventory (BDI), and the State-Trait Anxiety Inventory (STAI). The scores of the HADS depression and anxiety subscales were correlated with the BDI and STAI scores, and the rates of above-threshold scores were calculated and compared between the three questionnaires and findings from previous studies. RESULTS: The two HADS subscales significantly correlated with and the BDI (rs = .69, p < 0.001) and STAI state and trait anxiety (rs = .853, p < 0.001; r s = .744, p < 0.001, respectively). The usual HADS cut-off scores yielded adequate rate of anxiety but lower than expected depression rates. CONCLUSIONS: Our findings suggest the HADS as a valid screening tool for anxiety and depression in IBD patients. We recommend administering it routinely in gastrointestinal (GI) follow-ups using a lower cut-off score for depression than anxiety (greater than 7 vs greater than 11, respectively).

Blood brain barrier permeability increases with age in individuals with 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is characterised by high rates of psychotic disorders and immune abnormalities. Blood-brain barrier (BBB) permeability is known to be a risk factor for schizophrenia and immune aberrations. OBJECTIVE: To evaluate the relationship between psychosis and BBB permeability in this population. METHODS: We examined two biomarkers for BBB permeability, s100ß and neuron-specific enolase (NSE), in 22q11.2DS individuals with/without psychosis. The first cohort of this Israeli-Belgium study was comprised of 20 22q11.2DS adults (30.58 ± 9.42 years) afflicted with a psychotic disorder, another group of 69 non-psychotic 22q11.2DS adults (23.42 ± 8.36 years), and 58 healthy controls (26.39 ± 7.77 years). A second cohort was comprised of 18 non-psychotic 22q11.2DS Israeli children (5.83 ± 1.55 years) and 14 healthy controls (5.34 ± 1.43 years). NSE and s100ß serum levels were detected in all participants. RESULTS: Both factors were elevated in adults with 22q11.2DS compared to healthy controls, specifically in the non-psychotic sub-group. In contrast, there were no significant differences in their levels between the two groups of the paediatric cohort. CONCLUSIONS: Increased BBB permeability seems to be a trait of 22q11.2DS that evolves sometime in early adulthood. Our findings are in line with previous reports on non-syndromic schizophrenia, and suggest potential novel neural pathways to psychosis in 22q11.2DS.

Relationship between intelligence quotient measures and computerized neurocognitive performance in 22q11.2 deletion syndrome.

Intelligence quotient (IQ) testing is standard for evaluating cognitive abilities in genomic studies but requires professional expertise in administration and interpretation, and IQ scores do not translate into insights on implicated brain systems that can link genes to behavior. Individuals with 22q11.2 deletion syndrome (22q11.2DS) often undergo IQ testing to address special needs, but access to testing in resource-limited settings is challenging. The brief Penn Computerized Neurocognitive Battery (CNB) provides measures of cognitive abilities related to brain systems and can screen for cognitive dysfunction. To examine the relation between CNB measures and IQ, we evaluated participants with the 22q11.2DS from Philadelphia and Tel Aviv (N = 117; 52 females; mean age 18.8) who performed both an IQ test and the CNB with a maximum of 5 years between administrations and a subsample (n = 24) who had both IQ and CNB assessments at two time points. We estimated domain-level CNB scores using exploratory factor analysis (including bifactor for overall scores) and related those scores (intraclass correlations (ICCs)) to the IQ scores. We found that the overall CNB accuracy score showed similar correlations between time 1 and time 2 as IQ (0.775 for IQ and 0.721 for CNB accuracy), correlated well with the IQ scores (ICC = 0.565 and 0.593 for time 1 and time 2, respectively), and correlated similarly with adaptive functioning (0.165 and 0.172 for IQ and CNB, respectively). We provide a crosswalk (from linear equating) between standardized CNB and IQ scores. Results suggest that one can substitute the CNB for IQ testing in future genetic studies that aim to probe specific domains of brain-behavior relations beyond IQ.

Neutrophils to lymphocytes ratio and psychosis in 22q11.2 deletion syndrome - Clinical and scientific implications.

BACKGROUND: Individuals with 22q11.2 deletion syndrome (22q11.2DS) are at risk for having both psychotic and immune disorders, thus, implying a possible link between the two. The aim of the current study was to evaluate the usefulness of the neutrophiles to leukocytes ratio (NLR), an inflammatory marker, as a bio-marker for overt and prodromal psychotic symptoms in 22q11.2DS. METHODS: Forty-nine individuals with 22q11.2DS (13 with psychotic disorders and 36 without psychotic disorders) and 30 age- and sex-matched healthy controls underwent psychiatric evaluation using a structured psychiatric interview, the Scale of Prodromal Symptoms (SOPS) and the Global Assessment of Functioning (GAF) scale. Blood samples were collected from all participants on the day of assessment. NLR was calculated, compared among the study groups and correlated with SOPS and GAF scores. The non-psychotic 22q11.2DS group was further divided into high- and low-inflammation groups by NLR values and the analyses were done again. RESULTS: NLR was higher in the psychotic- and the high-inflammation non-psychotic 22q11.2DS groups compared to the low-inflammation non-psychotic 22q11.2DS group and controls. In the high-inflammation non-psychotic 22q11.2DS group NLR increase was associated with an increase of total negative symptoms scores on SOPS and a decrease in GAF scores. CONCLUSION: Our results suggest the potential utility of NLR as a bio-marker for psychotic disorders and subthreshold prodromal symptoms in 22q11.2DS. Furthermore, they imply that a disequilibrium between the innate and adaptive arms of the immune system facilitates the progression of psychosis in at risk populations. Further longitudinal studies are warranted to validate our findings, as this was a cross sectional observation.

Differential methylation of imprinting genes and MHC locus in 22q11.2 deletion syndrome-related schizophrenia spectrum disorders.

OBJECTIVES: 22q11.2 deletion syndrome (DS) is the strongest known genetic risk for schizophrenia. Methylome screening was conducted to elucidate possible involvement of epigenetic alterations in the emergence of schizophrenia spectrum disorders (SZ-SD) in 22q11.2DS. METHODS: Sixteen adult men with/without SZ-SD were recruited from a 22q11.2DS cohort and underwent genome-wide DNA methylation profile analysis. Differentially methylated probes (DMPs) and regions (DMRs) were analysed using the ChAMP software. RESULTS: The DMPs (p-value <10-6) and DMRs (p-valueArea <0.01) were enriched in two gene sets, 'imprinting genes' and 'chr6p21', a region overlapping the MHC locus. Most of the identified imprinting genes are involved in neurodevelopment and located in clusters under imprinting control region (ICR) regulation, including PEG10, SGCE (7q21.3), GNAS, GNAS-AS1 (20q13.32) and SNHG14, SNURF-SNRPN, SNORD115 (15q11.2). The differentially methylated genes from the MHC locus included immune HLA-genes and non-immune genes, RNF39, PPP1R18 and NOTCH4, implicated in neurodevelopment and synaptic plasticity. The most significant DMR is located in MHC locus and covered the transcription regulator ZFP57 that is required for control and maintenance of gene imprinting at multiple ICRs. CONCLUSIONS: The differential methylation in imprinting genes and in chr6p21-22 indicate the neurodevelopmental nature of 22q11.2DS-related SZ and the major role of MHC locus in the risk to develop SZ.

A three-tier process for screening depression and anxiety among children and adolescents with cancer.

OBJECTIVE: To establish and to evaluate the effectiveness of a three-tier screening process of depressive and anxiety disorders among children and adolescents with cancer based on questionnaires (first tier), semistructured psychiatric interviews (second tier), and referral for psychiatric assessment and recommendations for treatment (third tier). We also aimed to determine the rates of depressive and anxiety disorders among participants. METHODS: Participants and their parents completed the Patient Reported Outcomes Measurement Information System (PROMIS) Depression and Anxiety modules. Then, they were interviewed separately using the semistructured Affective and Anxiety Modules of the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS). PROMIS cutoff values for diagnosing depressive and anxiety disorders, based on the K-SADS, were calculated by receiver-operating characteristics (ROCs). RESULTS: Of 91 participants 34 (37.4%) aged 7 to 21 years with cancer met the K-SADS criteria for depressive and/or anxiety disorders. The results of the ROC analyses were stronger for depressive disorders than for anxiety disorders and for more severe cases. The cutoff of 13 on the child-reported PROMIS for a major depressive episode had a sensitivity of 0.80 and a specificity of 0.82, and a cutoff of 14 on the parent-reported PROMIS for generalized anxiety disorder had a sensitivity of 0.78 and a specificity of 0.79. CONCLUSIONS: Using the K-SADS, we found that anxiety and depressive disorders are very common in youngsters with cancer. The three-tier screening process we developed for depression and anxiety in this population provides practical cutoff values for identifying depressive and anxiety disorders in children with cancer.

Reducing Stigma Toward Psychiatry Among Medical Students: A Multicenter Controlled Trial.

OBJECTIVE: To examine the effect of a novel antistigma intervention curriculum (ASIC) in reducing stigma toward psychiatry among medical students. METHODS: Medical students from 8 hospitals in central Israel were divided into intervention (n = 57) and control (n = 163) arms. The students completed the 30-item Attitudes Toward Psychiatry (ATP-30) and the Attitudes Toward Mental Illness (AMI) scales at psychiatry rotation onset and conclusion. The ASIC was designed to target prejudices and stigma through direct informal encounters with people with serious mental illness (SMI) during periods of remission and recovery. Supervised small-group discussions followed those encounters to facilitate processing of thoughts and emotions that ensued and to discuss salient topics in psychiatry. The study was conducted between November 2017 and July 2018. RESULTS: Significant between-group differences were found at endpoint for attitudes toward psychiatry and psychiatric patients (P < .001). Although changing attitudes toward psychiatry as a career choice was not part of the ASIC, a significant between-group difference emerged by endpoint (P < .001). CONCLUSIONS: Implementation of an ASIC that includes contact with individuals with lived SMI experience followed by supervised small-group discussions is effective in reducing stigma in medical students' perceptions of people with mental illness and psychiatry. Further evaluation is warranted with regard to the long-term destigmatizing effects of an ASIC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03907696.

Exploring the potential association among sleep disturbances, cognitive impairments, and immune activation in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.DS) is a neurogenetic disorder caused by a microdeletion in chromosome 22. Its phenotype includes high rates of psychiatric disorders, immune system abnormalities, and cognitive impairments. We assessed the quality of sleep in 22q11.2DS and its potential link to inflammatory markers and cognitive deficits. Thirty-three 22q11.2DS individuals and 24 healthy controls were studied. Sleep parameters were assessed by the Pittsburgh sleep quality index (PSQI) questionnaire and correlated with serum cytokine levels and cognitive functioning, measured using the Penn computerized neurocognitive battery (CNB). The 22q11.2DS individuals had significantly worse sleep quality scores than the controls, unrelated to the psychiatric or physical comorbidities common to 22q11.2DS. Interleukin 6 levels were correlated with the overall score of the PSQI questionnaire for nonpsychotic 22q11.2DS participants only. Several domains of the CNB were associated with poorer sleep quality, suggesting that cognitive impairments in 22q11.2DS may be at least partially explained by poor sleep quality. Our findings confirm sleep impairments in individuals with 22q11.2DS, which might negatively affect their cognitive functioning, and corroborate a potential role of immunological pathways in the 22q11.2DS neuro-phenotype.

Elevated Proinflammatory Markers in 22q11.2 Deletion Syndrome Are Associated With Psychosis and Cognitive Deficits.

OBJECTIVE: 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder whose phenotype includes high rates of a schizophrenia-like psychotic disorder and immune system abnormalities. Thus, 22q11.2DS is an ideal model for studying the relationship between psychosis and inflammation. The aim of the present study was to identify inflammatory markers that may play a role in the pathophysiologic pathways associated with psychosis and cognitive deficits in 22q11.2DS. METHODS: Forty-nine individuals with 22q11.2DS (13 with psychotic disorders according to DSM-IV criteria and 36 without psychotic disorders) and 30 age- and sex-matched healthy controls underwent psychiatric and cognitive assessments at an outpatient clinic. Blood samples from all participants were analyzed for C-reactive protein (CRP), interleukin (IL)-6, IL-10, tumor necrosis factor alpha (TNFα), and IL-1 receptor antagonist levels. The study was conducted between August 2014 and September 2015. RESULTS: The 22q11.2DS participants had elevated levels of CRP (P = .004), IL-6 (P = .001), TNFα (P < .001), and IL-10 (P = .028) compared with controls. Furthermore, the psychotic 22q11.2DS participants had higher levels of IL-6 (P < .001) and IL-6/IL-10 ratio (used as an indicator for proinflammatory activation, P < .001) compared with the nonpsychotic 22q11.2DS individuals and controls. IL-6 levels and the IL-6/IL-10 ratio correlated with the severity of the cognitive deficits in the 22q11.2DS participants. CONCLUSIONS: Our preliminary findings indicate an involvement of inflammatory processes in the pathophysiology of psychosis and cognitive deficits in 22q11.2DS and are in line with the accumulating evidence for the role of neuroinflammation in nonsyndromic schizophrenia.

Negative subthreshold psychotic symptoms distinguish 22q11.2 deletion syndrome from other neurodevelopmental disorders: A two-site study.

About one third of individuals with 22q11.2 deletion syndrome (22q11.2DS) develop schizophrenia. Notably, a full-blown psychotic disorder is usually preceded by subthreshold symptoms. Therefore, it is important to identify early signs of psychosis in this population, a task that is complicated by the intellectual disabilities typically seen in 22q11.2DS. We aimed to identify subthreshold psychotic symptoms that distinguish 22q11.2DS from other neurodevelopmental disorders. The study included two independent cohorts from Tel Aviv and Philadelphia. 22q11.2DS (N=171) and typically developing (TD; N=832) individuals were enrolled at both sites and further compared to two groups with intellectual disabilities: Williams syndrome (WS; N=21) in the Tel Aviv cohort and idiopathic developmental disabilities (IDD; N=129) in the Philadelphia cohort. Participants and their primary caregivers were interviewed with the Structured Interview for Prodromal Symptoms (SIPS) and psychopathologies were assessed using standardized tools; general cognitive abilities were assessed with the Computerized Neurocognitive Battery. Negative/disorganized subthreshold syndrome was significantly more common in the 22q11.2DS group than in the WS (OR=3.90, 95% CI=1.34-11.34) or IDD (OR=5.05, 95% CI=3.01-10.08) groups. The 22q11.2DS group had higher scores than the two intellectual disabilities groups on several SIPS negative items, including avolition and decreased expression of emotion. Overall, there were few significant correlations between level of cognitive deficits and severity of negative symptoms in 22q11.2DS and only in the Tel Aviv cohort. Our findings suggest that 22q11.2DS individuals at the age of risk for developing psychosis should be closely monitored for negative symptoms.