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ObjectiveThe study's primary aim was to compare the utilization rates of services by minors with depression/anxiety in a county mental health clinic before (from December 1, 2019, to March 15, 2020) and during the COVID-19 pandemic (from March 16 to June 30, 2020). The secondary aim was to study demographics and psychiatric symptomatology.MethodsService utilization rates were estimated. Univariate and multivariate logistic regression was used to identify significant predictors of worsening psychiatric symptoms, anxiety, and change in the frequency of therapy between the pre-COVID-19 period and the COVID-19 period.ResultsService utilization rates increased during the pandemic period. During the pandemic, the presence of mood symptoms, suicidal ideation, and relationship conflicts predicted worsening psychiatric symptoms. In addition, the presence of preexisting sleep problems and physical health issues that continued during COVID-19 exhibited correlations with worsening psychiatric symptoms during COVID-19. COVID-related stressors and physical health issues were associated with anxiety; suicidal ideation predicted a change in the frequency of therapy.Conclusions Prospective studies to recognize risk factors for worsening mental health in minors with psychiatric illness during a crisis are warranted to identify and allocate services to the high-risk groups.

The biological mechanisms underlying the onset of major depressive disorder (MDD) have predominantly been studied in adult populations from high-income countries, despite the onset of depression typically occurring in adolescence and the majority of the world's adolescents living in low- and middle-income countries (LMIC). Taking advantage of a unique adolescent sample in an LMIC (Brazil), this study aimed to identify biological pathways characterizing the presence and increased risk of depression in adolescence, and sex-specific differences in such biological signatures. We collected blood samples from a risk-stratified cohort of 150 Brazilian adolescents (aged 14-16 years old) comprising 50 adolescents with MDD, 50 adolescents at high risk of developing MDD but without current MDD, and 50 adolescents at low risk of developing MDD and without MDD (25 females and 25 males in each group). We conducted RNA-Seq and pathway analysis on whole blood. Inflammatory-related biological pathways, such as role of hypercytokinemia/hyperchemokinemia in the pathogenesis of influenza (z-score = 3.464, p < 0.001), interferon signaling (z-score = 2.464, p < 0.001), interferon alpha/beta signaling (z-score = 3.873, p < 0.001), and complement signaling (z-score = 2, p = 0.002) were upregulated in adolescents with MDD compared with adolescents without MDD independently from their level of risk. The up-regulation of such inflammation-related pathways was observed in females but not in males. Inflammatory-related pathways involved in the production of cytokines and in interferon and complement signaling were identified as key indicators of adolescent depression, and this effect was present only in females.

BackgroundPeople with serious mental illnesses (SMIs) have three-fold higher rates of comorbid insomnia than the general population, which has downstream effects on cognitive, mental, and physical health. Cognitive Behavioral Therapy for Insomnia (CBT-i) is a safe and effective first-line treatment for insomnia, though the therapy's effectiveness relies on completing nightly sleep diaries which can be challenging for some people with SMI and comorbid cognitive deficits. Supportive technologies such as mobile applications and sleep sensors may aid with completing sleep diaries. However, commercially available CBT-i apps are not designed for individuals with cognitive deficits. To aid with this challenge, we have developed an integrated mobile application, named "Sleep Catcher," that will automatically incorporate data from a wearable fitness tracker and a bed sensor to track nightly sleep duration, overnight awakenings, bed-times, and wake-times to generate nightly sleep diaries for CBT-i.MethodsThe application development process will be described-writing algorithms to generating useful data, creating a clinician web portal to oversee patients and the mobile application, and integrating sleep data from device platforms and user input.ResultsThe mobile and web applications were developed using Flutter, IBM Code Engine, and IBM Cloudant database. The mobile application was developed with a user-centered approach and incremental changes informed by a series of beta tests. Special user-interface features were considered to address the challenges of developing a simple and effective mobile application targeting people with SMI.ConclusionThere is strong potential for synergy between engineering and mental health expertise to develop technologies for specific clinical populations. Digital health technologies allow for the development of multi-disciplinary solutions to existing health disparities in vulnerable populations, particularly in people with SMI.

BackgroundAlthough social rejection is among the strongest proximal precipitants of major depressive disorder (MDD), little is known about the underlying neurobiological mechanisms and whether neural sensitivity to social rejection may help explain differences in MDD risk. To address this issue, we tested whether neural responses to social threat differed in female adolescents at high vs. low maternal risk for MDD.MethodFemale adolescents with (high-risk; n = 22, Mage = 14.68) and without (low-risk; n = 30, Mage = 15.07) a maternal history of depression were experimentally exposed to negative and neutral social evaluation while undergoing an fMRI scan. Neural responses were assessed by event-related activity and functional connectivity, as well as multivoxel pattern analysis. Activity and functional connectivity analyses focused on a priori-selected regions of interest implicated in self-referential processing and emotion regulation.ResultsCompared to low-risk female adolescents, high-risk female adolescents exhibited greater increases in self-reported depression and social disconnection following social evaluation. Moreover, compared to low-risk female adolescents, high-risk female adolescents exhibited greater amygdala responses to negative social evaluation and a differential pattern of functional connectivity in brain regions related to emotion regulation, self-referential processing, and negative affect. Additionally, these markers of neural threat reactivity were related to depressive symptoms.LimitationsA cross-sectional study design and relatively small, Western sample.ConclusionsThese results suggest that exaggerated neural reactivity to social threat-and an atypical pattern of related functional connectivity-is evident in individuals with a preclinical risk factor for depression. Targeting such responding may thus be a fruitful strategy for preventing depression in at-risk youth.

Screening for psychosis spectrum disorders in primary care could improve early identification and reduce the duration of untreated psychosis. However, the accuracy of psychosis screening in this setting is unknown. To address this, we conducted a diagnostic accuracy study of screening for psychosis spectrum disorders in eight behavioral health services integrated into primary care clinics. Patients attending an integrated behavioral health appointment at their primary care clinic completed the Prodromal Questionnaire - Brief (PQ-B) immediately prior to their intake assessment. This was compared to a diagnostic phone interview based on the Structured Interview for Psychosis Risk Syndromes (SIPS). In total, 145 participants completed all study procedures, of which 100 screened positive and 45 negative at a provisional PQ-B threshold of ≥20. The PQ-B was moderately accurate at differentiating psychosis spectrum from no psychosis spectrum disorders; a PQ-B distress score of ≥27 had a sensitivity and specificity of 71.2 % and 57.0 % respectively. In total, 66 individuals (45.5 %) met criteria for a psychosis spectrum disorder and 24 (16.7 %) were diagnosed with full psychosis, indicating a high prevalence of psychosis in the sample. Overall, screening for psychosis spectrum disorders in an IBH primary care setting identified a relatively high number of individuals and may identify people that would otherwise be missed. The PQ-B performed slightly less well than in population-based screening in community mental health settings. However, the findings suggest this may represent an effective way to streamline the pathway between specialty early psychosis programs and primary care clinics for those in need.

Genome-wide association studies (GWASs) have uncovered susceptibility loci associated with psychiatric disorders such as bipolar disorder (BP) and schizophrenia (SCZ). However, most of these loci are in non-coding regions of the genome, and the causal mechanisms of the link between genetic variation and disease risk is unknown. Expression quantitative trait locus (eQTL) analysis of bulk tissue is a common approach used for deciphering underlying mechanisms, although this can obscure cell-type-specific signals and thus mask trait-relevant mechanisms. Although single-cell sequencing can be prohibitively expensive in large cohorts, computationally inferred cell-type proportions and cell-type gene expression estimates have the potential to overcome these problems and advance mechanistic studies. Using bulk RNA-seq from 1,730 samples derived from whole blood in a cohort ascertained from individuals with BP and SCZ, this study estimated cell-type proportions and their relation with disease status and medication. For each cell type, we found between 2,875 and 4,629 eGenes (genes with an associated eQTL), including 1,211 that are not found on the basis of bulk expression alone. We performed a colocalization test between cell-type eQTLs and various traits and identified hundreds of associations that occur between cell-type eQTLs and GWASs but that are not detected in bulk eQTLs. Finally, we investigated the effects of lithium use on the regulation of cell-type expression loci and found examples of genes that are differentially regulated according to lithium use. Our study suggests that applying computational methods to large bulk RNA-seq datasets of non-brain tissue can identify disease-relevant, cell-type-specific biology of psychiatric disorders and psychiatric medication.

Recent studies have highlighted the essential role of RNA splicing, a key mechanism of alternative RNA processing, in establishing connections between genetic variations and disease. Genetic loci influencing RNA splicing variations show considerable influence on complex traits, possibly surpassing those affecting total gene expression. Dysregulated RNA splicing has emerged as a major potential contributor to neurological and psychiatric disorders, likely due to the exceptionally high prevalence of alternatively spliced genes in the human brain. Nevertheless, establishing direct associations between genetically altered splicing and complex traits has remained an enduring challenge. We introduce Spliced-Transcriptome-Wide Associations (SpliTWAS) to integrate alternative splicing information with genome-wide association studies to pinpoint genes linked to traits through exon splicing events. We applied SpliTWAS to two schizophrenia (SCZ) RNA-sequencing datasets, BrainGVEX and CommonMind, revealing 137 and 88 trait-associated exons (in 84 and 67 genes), respectively. Enriched biological functions in the associated gene sets converged on neuronal function and development, immune cell activation, and cellular transport, which are highly relevant to SCZ. SpliTWAS variants impacted RNA-binding protein binding sites, revealing potential disruption of RNA-protein interactions affecting splicing. We extended the probabilistic fine-mapping method FOCUS to the exon level, identifying 36 genes and 48 exons as putatively causal for SCZ. We highlight VPS45 and APOPT1, where splicing of specific exons was associated with disease risk, eluding detection by conventional gene expression analysis. Collectively, this study supports the substantial role of alternative splicing in shaping the genetic basis of SCZ, providing a valuable approach for future investigations in this area.

BACKGROUND AND HYPOTHESIS: People with serious mental illness (SMI; psychotic and affective disorders with psychosis) are at an increased risk of suicide, yet there is limited research on the correlates of suicide in SMI. Social cognitive impairments are common among people with SMI and several studies have examined social cognition and suicidal ideation (SI) and behavior. This systematic review aims to evaluate the links between various domains of social cognition, SI, and suicidal behavior in SMI. STUDY DESIGN: Electronic databases (PubMed and PsycInfo) were searched through June 2023. Records obtained through this search (N = 618) were screened by 2 independent reviewers according to inclusion criteria. Relevant data were extracted, and study quality was assessed. STUDY RESULTS: Studies (N = 16) from 12 independent samples were included in the systematic review (N = 2631, sample sizes ranged from N = 20 to N = 593). Assessments of social cognition and SI and behavior varied widely between studies. Broadly, effects were mixed. Better emotion recognition of negative affect was linked to SI and a history of suicide attempts, though there is little consistent evidence for the relationship of emotion recognition and SI or behavior. On the other hand, better theory of mind ability was linked to SI and a history of suicide attempts. Furthermore, negative attributional bias was linked to current SI, but not a history of SI or attempt. CONCLUSIONS: This review suggests mixed associations between social cognition, SI, and behavior in SMI. Future research should evaluate additional mediators and moderators of social cognition and suicide, employing prospective designs.

The well-being and satisfaction of individuals with serious mental illnesses (SMI) and their family caregivers are less than desirable. Research on the quality of life (QoL) of individuals with SMI and their caregivers, including disorders other than schizophrenia, is limited. Thus, this study aimed to investigate the self-perception of QoL in patients with SMI and their family caregivers and the associated factors. This cross-sectional study was conducted in patients with SMI and their caregivers who completed self-assessment instruments to determine their QoL. Social support and burden in caregivers and symptomatology levels in individuals with SMI were assessed. The physical aspect of QoL in individuals with SMI was associated with employment status and symptom severity. The physical component of caregivers’ QoL was associated with kinship relationship, the presence of other family members with disabilities, social support, and age. The mental component was associated with global symptomatology and the diagnosis of major depression in individuals with SMI and caregiver burden in family members. In conclusion, these findings on correlated factors of QoL in individuals with SMI and their caregivers could be used in developing therapeutic interventions for mental health. Plain summary: A significant number of people with serious mental health problems and their families often endure poor quality of life. However, research on how these individuals truly feel about their lives is limited. This study aimed to explore the perceptions of quality of life among individuals with serious mental health issues and their family caregivers in Spain. We sought to understand the personal sentiments of these individuals and their caregivers regarding their quality of life and the factors that influence it. Our findings indicate that job status, symptoms of the illness, and family relationships play crucial roles in how these individuals view their quality of life. Additionally, car

The COVID-19 pandemic inspired calls for rapid decarceration of prisons and jails to slow the spread of disease in a high-risk congregate setting. Due to the rarity of intentionally-decarcerative policies, little is known about the effects of rapid decarceration on individuals with serious mental illness (SMI) substance use disorder (SUD), a population who receive many services via the criminal legal system (CLS). We conducted interviews with 13 key informants involved in CLS in San Francisco, CA to better understand the implication of the decarcerative policies put into practice in early 2020. Participants described a tension between the desire to have fewer people incarcerated and the challenges of accessing services and support - especially during the lockdown period of the pandemic - outside of the CLS given the number of services that are only accessible to those who have been arrested, incarcerated, or sentenced. These findings emphasize the need for investing in community social services rather than further expanding the CLS to achieve the goal of supporting individuals with SMI and SUD shrinking the US system of mass incarceration.

ObjectiveFood insecurity is defined as lack of consistent access to adequate food for healthy living. The objective of this study was to determine the associations between food insecurity and binge-eating disorder in a national cohort of 9- to 14-year-old children.MethodWe analyzed prospective cohort data from the Adolescent Brain Cognitive Development (ABCD) Study (N = 10,035, 2016-2020). Logistic regression analyses estimated the associations between food insecurity at baseline, year 1, or year 2 (exposure) and binge eating, subclinical binge-eating disorder (Other Specified Feeding and Eating Disorder-Binge-Eating Disorder [OSFED-BED]), and binge-eating disorder (BED) (outcome) based on the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS-5) at 2-year follow-up.ResultsThe prevalence of food insecurity in the study was 15.8%. At 2-year follow-up, 1.71% of the sample received a diagnosis of BED or OSFED-BED, while 6.62% reported binge eating. Food insecurity was associated with 1.67 higher odds of BED or OSFED-BED (95% CI 1.04-2.69) and 1.31 higher odds of binge-eating symptoms (95% CI 1.01-1.71).DiscussionFood insecurity in early adolescence is associated with higher odds of developing future binge-eating and BED or OSFED-BED. Clinicians may consider assessing for binge eating in adolescents with food insecurity and provide support in accessing appropriate food resources.Public significancePrior research has shown that food insecurity is associated with disordered eating behaviors, including binge eating in adulthood. This study explored whether food insecurity in early adolescence increases risk for developing binge-eating disorder (BED). Targeted screening for BED in adolescents experiencing FI, and vice versa, may be warranted.

ObjectiveThe StRONG study demonstrated that higher calorie refeeding (HCR) restored medical stability faster in patients hospitalized with anorexia nervosa (AN) and atypical AN (AAN), with no increased safety events compared with standard-of-care lower calorie refeeding (LCR). However, some clinicians have expressed concern about potential unintended consequences of HCR (e.g., greater mealtime distress). The purpose of this study was to examine patient treatment preference and compare mealtime distress, food refusal, and affective states between treatments.MethodParticipants (N = 111) in this multisite randomized clinical trial were ages 12-24 years, with AN or AAN, admitted to hospital with medical instability who received assigned study treatment (HCR or LCR). Treatment preference was assessed prior to randomization in the full sample. In a subset of participants (n = 45), linear mixed effect models were used to analyze momentary ratings of mealtime distress (pre, during, and post-meals) and daily affective state during the hospitalization.ResultsAbout half (55%) of participants reported a preference for LCR. Treatment assignment was not associated with food refusal, mealtime distress, or affective states in the subsample. Food refusal increased significantly over the course of refeeding (p = .018). Individuals with greater depression experienced more negative affect (p = .033), with worsening negative affect over time for individuals with higher eating disorder psychopathology (p = .023).DiscussionDespite understandable concerns about potential unintended consequences of HCR, we found no evidence that treatment acceptability for HCR differed from LCR for adolescents and young adults with AN and AAN.Public significanceThe efficacy and safety of higher calorie refeeding in hospitalized patients with anorexia nervosa has been demonstrated. However, it is not known whether higher calorie refeeding (HCR) increases meal

BackgroundEpidemiological studies suggest that maternal immune activation (MIA) is a significant risk factor for future neurodevelopmental disorders, including schizophrenia (SZ), in offspring. Consistent with findings in SZ research and work in rodent systems, preliminary cross-sectional findings in nonhuman primates suggest that MIA is associated with dopaminergic hyperfunction in young adult offspring.MethodsIn this unique prospective longitudinal study, we used [18F]fluoro-l-m-tyrosine positron emission tomography to examine the developmental time course of striatal presynaptic dopamine synthesis in male rhesus monkeys born to dams (n = 13) injected with a modified form of the inflammatory viral mimic, polyinosinic:polycytidylic acid [poly(I:C)], in the late first trimester. Striatal (caudate, putamen, and nucleus accumbens) dopamine from these animals was compared with that of control offspring born to dams that received saline (n = 10) or no injection (n = 4). Dopamine was measured at 15, 26, 38, and 48 months of age. Prior work with this cohort found decreased prefrontal gray matter volume in MIA offspring versus controls between 6 and 45 months of age. Based on theories of the etiology and development of SZ-related pathology, we hypothesized that there would be a delayed (relative to the gray matter decrease) increase in striatal fluoro-l-m-tyrosine signal in the MIA group versus controls.Results[18F]fluoro-l-m-tyrosine signal showed developmental increases in both groups in the caudate and putamen. Group comparisons revealed significantly greater caudate dopaminergic signal in the MIA group at 26 months.ConclusionsThese findings are highly relevant to the known pathophysiology of SZ and highlight the translational relevance of the MIA model in understanding mechanisms by which MIA during pregnancy increases risk for later illness in offspring.

BackgroundDysfunctional cognitive control processes are now well understood to be core features of schizophrenia (SZ). A body of work suggests that the dorsolateral prefrontal cortex (DLPFC) plays a critical role in explaining cognitive control disruptions in SZ. Here, we examined relationships between DLPFC activation and drift rate (DR), a model-based performance measure that combines reaction time and accuracy, in people with SZ and healthy control (HC) participants.MethodsOne hundred fifty-one people with recent-onset SZ spectrum disorders and 118 HC participants performed the AX-Continuous Performance Task during functional magnetic resonance imaging scanning. Proactive cognitive control-associated activation was extracted from left and right DLPFC regions of interest. Individual behavior was fit using a drift diffusion model, allowing DR to vary between task conditions.ResultsBehaviorally, people with SZ showed significantly lower DRs than HC participants, particularly during high proactive control trial types ("B" trials). Recapitulating previous findings, the SZ group also demonstrated reduced cognitive control-associated DLPFC activation compared with HC participants. Furthermore, significant group differences were also observed in the relationship between left and right DLPFC activation with DR, such that positive relationships between DR and activation were found in HC participants but not in people with SZ.ConclusionsThese results suggest that DLPFC activation is less associated with cognitive control-related behavioral performance enhancements in SZ. Potential mechanisms and implications are discussed.

Patients with atypical anorexia nervosa (AAN) or anorexia nervosa (AN) with premorbid history of higher weight (PHW; median BMI ≥ 85th %ile) may report greater eating disorder (ED) pathology, anxiety, and depression, than patients with premorbid history of lower weight (PLW; mBMI <85th %ile). Less is known about caregiver attitudes or treatment outcome related to premorbid weight history. The current study examined associations between premorbid weight history and patient/caregiver factors at presentation, during treatment, and end of treatment among adolescents (N = 138) diagnosed with AN/AAN and their caregivers who received interdisciplinary ED treatment. The sample comprised adolescents with PHW (n = 58, 40.6 %) or PLW (n = 82, 59.4 %). Adolescents with PHW did not differ with regard to patient- or caregiver-reported ED symptoms, comorbid psychopathology, rates of treatment completion, and attainment of estimated body weight compared to PLW (ps > .05). Adolescents with PHW (vs. PLW) were more likely to be diagnosed with AAN (67.9 %, p < .001), identify as cisgender male (p < .001) and to have lost more weight prior to presentation (p < .001). Perceived caregiver burden was lower among adolescents with PHW vs. PLW (p < .001). Further research should expand on this preliminary study exploring associations between premorbid weight history on patient and caregiver factors at treatment presentation and conclusion to enhance the efficacy of evidence-based treatment across the weight-spectrum.

Objectives: When considering the personal recovery of people with serious mental illness (SMI), it is essential to examine their reported psychiatric distress and quality of life (QoL). However, there is no consolidated model in the literature that clearly relates these variables. In this study we first analysed the relationships between QoL, psychiatric distress and recovery, and several sociodemographic variables. Second, we analysed the linear effects of psychiatric distress and recovery on QoL. Third, and most important, we tested two hypotheses that considered personal recovery as a moderator or mediator of the relationship between psychiatric distress and QoL. Design and Methods: 234 volunteers with a diagnosis of SMI completed three self-report questionnaires, The Recovery Assessment Scale-24, The World Health Organization QoL and the Clinical Outcomes in Routine Evaluation-Outcome Measure, which showed very good levels of validity and reliability. The PROCESS macro for SPSS developed by Hayes (Introduction to mediation, moderation, and conditional process analysis: A regression-based approach, The Guilford Press, 2022) was applied using the Bootstrap method to verify our moderation and mediation hypotheses. Results: We found a negative linear effect of psychiatric distress on QoL, as well as a positive effect of recovery on said variable. Our results do not confirm the moderating effect of recovery on the relationship between distress and QoL. However, we do confirm the second hypothesis; recovery functioned as a mediating variable between psychiatric distress and QoL. Conclusions: These findings allow us to reflect on how personal recovery affect the relationship between psychiatric distress and QoL and discuss its theoretical and practical implications as public policies.

Eating disorders (EDs) are complex psychiatric diagnoses requiring specialized care. Family-based treatment (FBT) is the first-line treatment for adolescent anorexia nervosa and is also efficacious for other EDs. This study describes practice changes due to the implementation of an integrated interdisciplinary FBT-aligned treatment program for EDs at a large tertiary care hospital in the United States. We examined the feasibility and acceptability of implementation, barriers to implementation, and impact on providers' roles over a one-year period. Practice changes came with shifts in roles, and were largely experienced as acceptable with good suitability. Barriers identified may inform future interdisciplinary implementation efforts.

PurposeCaregivers play a pivotal role in the success of family-based treatment (FBT) for anorexia nervosa (AN). Caregiver burden is frequently demonstrated in eating disorders (EDs) and may impact FBT outcomes. This study examined factors associated with caregiver burden before starting FBT and whether pre-treatment caregiver burden was associated with weight gain during FBT.MethodsParticipants included 114 adolescents with AN or atypical AN (mean age = 15.6 years, SD = 1.4) and a primary caregiver (87.6% mothers) who received FBT in the United States. Before starting treatment, participants completed self-report measures of caregiver burden (via the Eating Disorder Symptom Impact Scale), caregiver anxiety, caregiver depression, and ED symptoms. Clinical characteristics and percentage of target goal weight (%TGW) at FBT session 1 and 3 and 6 months after starting treatment were obtained via retrospective chart review. Hierarchical regressions examined predictors of caregiver burden before FBT initiation. Associations between pre-treatment caregiver burden and %TGW gain at 3 and 6 months after starting FBT were assessed with hierarchical regressions.ResultsCaregiver anxiety (p < 0.001), family history of EDs (p = 0.028), adolescent mental health treatment history (p = 0.024), and ED symptoms (p = 0.042) predicted caregiver burden before starting FBT. Pre-treatment caregiver burden was not associated with %TGW gain at 3 or 6 months. Males demonstrated less %TGW gain than females at 3 months (p = 0.010) and 6 months (p = 0.012).ConclusionProactively evaluating caregiver burden before starting FBT is suggested. Providing recommendations and/or referrals for identified caregiver vulnerabilities could indirectly impact FBT progress. Males in FBT could require longer courses of treatment and extra vigilance to this demographic is suggested.Level of evidenceLevel III, case-control analytic study.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

We describe a rare case of acute mania in the setting of autoimmune adrenalitis. A 41-year-old male with no previous psychiatric diagnoses presented with impulsivity, grandiosity, delusions of telepathy, and hyperreligiosity following a previous hospitalization for an acute adrenal crisis and 2 subsequent days of low-dose corticosteroid treatment. Workups for encephalopathy and lupus cerebritis were negative, raising concern that this presentation might represent steroid-induced psychosis. However, discontinuation of corticosteroids for 5 days did not resolve the patient's manic episode, suggesting that his clinical presentation was more likely new onset of a primary mood disorder or a psychiatric manifestation of adrenal insufficiency itself. The decision was made to restart corticosteroid treatment for the patient's primary adrenal insufficiency (formerly known as Addison disease), coupled with administration of both risperidone and valproate for mania and psychosis. Over the following 2 weeks, the patient's manic symptoms resolved, and he was discharged home. His final diagnosis was acute mania secondary to autoimmune adrenalitis. Although acute mania in adrenal insufficiency is quite rare, clinicians should be aware of the range of psychiatric manifestations associated with Addison disease so that they can pursue the optimal course of both medical and psychiatric treatment for these patients.

BackgroundSouth Africa's rates of psychiatric morbidity are among the highest in sub-Saharan Africa and are foregrounded by the country's long history of political violence during apartheid. Growing evidence suggests that in utero stress exposure is a potent developmental risk factor for future mental illness risk, yet the extent to which the psychiatric effects of prenatal stress impact the next generation are unknown. We evaluate the intergenerational effects of prenatal stress experienced during apartheid on psychiatric morbidity among children at ages 17-18 and also assess the moderating effects of maternal age, social support, and past household adversity.MethodsParticipants come from Birth-to-Twenty, a longitudinal birth cohort study in Soweto-Johannesburg, South Africa's largest peri-urban township which was the epicentre of violent repression and resistance during the final years of the apartheid regime. Pregnant women were prospectively enrolled in 1990 and completed questionnaires assessing social experiences, and their children's psychiatric morbidity were assessed at ages 17-18.ResultsFull data were available from 304 mother-child pairs in 2007-8. Maternal prenatal stress in 1990 was not directly associated greater psychiatric morbidity during at ages 17-18. Maternal age and past household adversity moderated the intergenerational mental health effects of prenatal stress such that children born to younger mothers and late adolescent/young adult children experiencing greater household adversity exhibited worse psychiatric morbidity at ages 17-18. Social support did not buffer against the long-term psychiatric impacts of prenatal stress.ConclusionsGreater prenatal stress from apartheid predicted adverse psychiatric outcomes among children born to younger mothers and adolescents/young adults who experienced greater concurrent stress. Our findings suggest that prenatal stress may affect adolescent mental health, have stress-sensitising effects, and represent

Intolerance of uncertainty (IU), the dispositional tendency to fear the unknown, has clinical implications across a variety of disorders. While research has linked IU and OCD, relatively little is known about this association. Previous studies have focused on IU’s association with overall OCD severity and specific symptom dimensions, but we do not yet understand to what degree this cognitive vulnerability is associated with each of the two cardinal symptoms: obsessions and compulsions. Additionally, few studies have examined the established IU subtypes—prospective and inhibitory IU—as unique contributors to OCD severity. Given the ubiquity of uncertainty in daily life and the potential for IU to influence obsessive-compulsive processes, further investigation of this cognitive vulnerability in OCD is warranted. In a sample of patients diagnosed with OCD, partial correlations were conducted to determine the association between OCD severity (separately examining obsessions and compulsions) and IU (separately examining prospective and inhibitory IU). These analyses revealed positive correlations between IU and compulsion severity, specifically. And of the IU subtypes, this link was specifically associated with prospective IU. The results of this correlational study contribute to the literature on IU in OCD, suggesting prospective IU as a cognitive mechanism that may be involved in the maintenance of compulsions.

BackgroundTheories suggest that people with schizophrenia (SZ) have problems generating predictions based on past experiences. The dorsolateral prefrontal cortex (DLPFC) and hippocampus participate in memory-based prediction. We used functional magnetic resonance imaging to investigate DLPFC and hippocampal function in healthy control (HC) subjects and people with SZ during memory-based prediction.MethodsPrior to scanning, HC subjects (n = 54) and people with SZ (n = 31) learned 5-object sequences presented in fixed or random orders on each repetition. During scanning, participants made semantic decisions (e.g., "Can this object fit in a shoebox?") on a continuous stream of objects from fixed and random sequences. Sequence prediction was demonstrated by faster semantic decisions for objects in fixed versus random sequences because memory could be used to anticipate and more efficiently process semantic information about upcoming objects in fixed sequences. Representational similarity analyses were used to determine how each sequence type was represented in the posterior hippocampus and DLPFC.ResultsSequence predictions were reduced in individuals with SZ relative to HC subjects. Representational similarity analyses revealed stronger memory-based predictions in the DLPFC of HC subjects than people with SZ, and DLPFC representations correlated with more successful predictions in HC subjects only. For the posterior hippocampus, voxel pattern similarity was increased for fixed versus random sequences in HC subjects only, but no significant between-group differences or correlations with prediction success were observed.ConclusionsIndividuals with SZ are capable of learning temporal sequences; however, they are impaired using memory to predict upcoming events as efficiently as HC subjects. This deficit appears related to disrupted neural representation of sequence information in the DLPFC.

BackgroundPre-treatment biomarkers for outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder (MDD) have proven elusive. One promising family of biomarkers involves the autonomic nervous system (ANS), which is dysregulated in individuals with MDD.MethodsWe examined the relationship between the pre-treatment pupillary light reflex (PLR) and rTMS outcome in 51 MDD patients. Outcome was measured as the percent change in the 30-item Inventory of Depressive Symptomatology Self Rated (IDS-SR) score from baseline to treatment 30.ResultsPatients showed significant improvement with rTMS treatment. There was a significant correlation between baseline pupillary Constriction Amplitude (CA) and clinical improvement over the treatment course (R = 0.41, p = 0.003).LimitationsWe examined a limited number of subjects who received heterogeneous treatment protocols. Almost all patients in the study received psychotropic medications concomitant with rTMS treatment.ConclusionPLR measured before treatment may be a predictive biomarker for clinical improvement from rTMS in subjects with MDD.

BackgroundWhile comorbidity of clinical high-risk for psychosis (CHR-P) status and social anxiety is well-established, it remains unclear how social anxiety and positive symptoms covary over time in this population. The present study aimed to determine whether there are more than one covariant trajectory of social anxiety and positive symptoms in the North American Prodrome Longitudinal Study cohort (NAPLS 2) and, if so, to test whether the different trajectory subgroups differ in terms of genetic and environmental risk factors for psychotic disorders and general functional outcome.MethodsIn total, 764 CHR individuals were evaluated at baseline for social anxiety and psychosis risk symptom severity and followed up every 6 months for 2 years. Application of group-based multi-trajectory modeling discerned three subgroups based on the covariant trajectories of social anxiety and positive symptoms over 2 years.ResultsOne of the subgroups showed sustained social anxiety over time despite moderate recovery in positive symptoms, while the other two showed recovery of social anxiety below clinically significant thresholds, along with modest to moderate recovery in positive symptom severity. The trajectory group with sustained social anxiety had poorer long-term global functional outcomes than the other trajectory groups. In addition, compared with the other two trajectory groups, membership in the group with sustained social anxiety was predicted by higher levels of polygenic risk for schizophrenia and environmental stress exposures.ConclusionsTogether, these analyses indicate differential relevance of sustained v. remitting social anxiety symptoms in the CHR-P population, which in turn may carry implications for differential intervention strategies.

BACKGROUND: Train-the-trainer (TTT) is a promising method for implementing evidence-based psychological treatments (EBPTs) in community mental health centers (CMHCs). In TTT, expert trainers train locally embedded individuals (i.e., Generation 1 providers) to deliver an EBPT, who then train others (i.e., Generation 2 providers). The present study will evaluate implementation and effectiveness outcomes of an EBPT for sleep and circadian dysfunction-the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C)-delivered to CMHC patients with serious mental illness by Generation 2 providers (i.e., trained and supervised within CMHCs via TTT). Specifically, we will investigate whether adapting TranS-C to fit CMHC contexts improves Generation 2 (a) patient outcomes and (b) providers perceptions of fit. METHODS: TTT will be implemented in nine CMHCs in California, USA (N = 60 providers; N = 130 patients) via facilitation. CMHCs are cluster-randomized by county to Adapted TranS-C or Standard TranS-C. Within each CMHC, patients are randomized to immediate TranS-C or usual care followed by delayed treatment with TranS-C (UC-DT). Aim 1 will assess the effectiveness of TranS-C (combined Adapted and Standard), compared to UC-DT, on improvements in sleep and circadian problems, functional impairment, and psychiatric symptoms for Generation 2 patients. Aim 2 will evaluate whether Adapted TranS-C is superior to Standard TranS-C with respect to Generation 2 providers perceptions of fit. Aim 3 will evaluate whether Generation 2 providers perceived fit mediates the relation between TranS-C treatment condition and patient outcomes. Exploratory analyses will (1) evaluate whether the effectiveness of TranS-C for patient outcomes is moderated by generation, (2) compare Adapted and Standard TranS-C on patient perceptions of credibility/improvement and PhenX Toolkit outcomes (e.g., substance use, suicidality), and (3) evaluate other possible moderators. DISCUSSION: Th

Most people with co-occurring opioid use disorder (OUD) and mental illness do not receive effective medications for treating OUD. To investigate perspectives of adults in a publicly-funded mental health system regarding medications for OUD (MOUD), we conducted semi-structured telephone interviews with 13 adults with OUD (current or previous diagnosis) receiving mental health treatment. Themes that emerged included: perceiving or using MOUDs as a substitute for opioids or a temporary solution to prevent withdrawal symptoms; negative perceptions about methadone/methadone clinics; and viewing MOUD use as "cheating". Readiness to quit was important for patients to consider MOUDs. All participants were receptive to discussing MOUDs with their mental health providers and welcomed the convenience of receiving care for their mental health and OUD at the same location. In conclusion, clients at publicly-funded mental health clinics support MOUD treatment, signaling a need to expand access and build awareness of MOUDs in these settings.

BackgroundPeople with schizophrenia experience unique barriers to routine HIV testing, despite increased risk of HIV compared to the general US population. Little is known about how healthcare delivery system factors impact testing rates or whether there are testing differences for people with schizophrenia.SettingNationally representative sample of Medicaid enrollees with and without schizophrenia.MethodsUsing retrospective longitudinal data, we examined whether state-level factors were associated with differences in HIV testing among Medicaid enrollees with schizophrenia compared to frequency matched controls during 2002-2012. Multivariable logistic regression estimated testing rate differences between and within cohorts.ResultsHigher HIV testing rates for enrollees with schizophrenia was associated with higher state-level Medicaid spending per enrollee, efforts to reduce Medicaid fragmentation, and higher federal prevention funding. State-level AIDS epidemiology predicted more frequent HIV testing for enrollees with schizophrenia versus controls. Living in rural settings predicted lower HIV testing, especially for people with schizophrenia.ConclusionOverall, state-level predictors of HIV testing rates varied among Medicaid enrollees, though rates were generally higher for those with schizophrenia than controls. Increased HIV testing for people with schizophrenia was associated with coverage of HIV testing when medically necessary, higher CDC prevention funding, and higher AIDS incidence, prevalence, and mortality when compared to controls. This analysis suggests that state policymaking has an important role to play in advancing that effort. Overcoming fragmented care systems, sustaining robust prevention funding, and consolidating funding streams in innovative and flexible ways to support more comprehensive systems of care delivery deserve attention.

Characterizing neuropsychiatric disorders is challenging due to heterogeneity in the population. We propose combining structural and functional neuroimaging and genomic data in a multimodal classification framework to leverage their complementary information. Our objectives are two-fold (i) to improve the classification of disorders and (ii) to introspect the concepts learned to explore underlying neural and biological mechanisms linked to mental disorders. Previous multimodal studies have focused on naïve neural networks, mostly perceptron, to learn modality-wise features and often assume equal contribution from each modality. Our focus is on the development of neural networks for feature learning and implementing an adaptive control unit for the fusion phase. Our mid fusion with attention model includes a multilayer feed-forward network, an autoencoder, a bi-directional long short-term memory unit with attention as the features extractor, and a linear attention module for controlling modality-specific influence. The proposed model acquired 92% (p < .0001) accuracy in schizophrenia prediction, outperforming several other state-of-the-art models applied to unimodal or multimodal data. Post hoc feature analyses uncovered critical neural features and genes/biological pathways associated with schizophrenia. The proposed model effectively combines multimodal neuroimaging and genomics data for predicting mental disorders. Interpreting salient features identified by the model may advance our understanding of their underlying etiological mechanisms.

Anxious traits are elevated in eating disorders (EDs), are considered risk factors for ED development, and trait anxiety has been linked to ED psychopathology. How trait anxiety relates to ED neurobiology is not well understood. In this study 197 individuals across the ED spectrum (anorexia nervosa n = 91; other specified EDs n = 34; bulimia nervosa n = 56; binge ED n = 16), and 120 healthy controls were assessed for anxious traits and learned to expect and receive caloric or neutral taste stimuli during brain imaging. Amygdala sucrose expectation response differed across groups (Wilk's lambda = 0.945, p = 0.023), and was higher on the left in anorexia nervosa compared to healthy controls (p = 0.002). Expected sucrose receipt response across taste reward regions was not different between groups. In the ED sample, trait anxiety negatively moderated the relationship between amygdala expectation and right dorsal (p = 0.0062) and ventral (p = 0.0046) anterior insula receipt response. A subgroup analysis showed similar results for anorexia nervosa, and partially in bulimia nervosa. Across EDs, appetitive motivation correlated positively with bilateral orbitofrontal cortex, caudate head, and ventral striatal sucrose receipt response (r = 0.215 to 0.179, p = 0.002 to 0.012). Across the study sample, trait anxiety showed an inverted-U-shaped relationship with right (r = 0.147, p = 0.034) and left (r = 0.162, p = 0.016) amygdala expectation response. Amygdala sucrose expectation response is elevated in anorexia nervosa, correlates with sucrose receipt response, and this relationship is negatively moderated by trait anxiety across EDs. Trait anxiety may have an important role in how expectation drives taste stimulus receipt brain response and perhaps food approach in individuals with EDs.

Feature selection can disclose biomarkers of mental disorders that have unclear biological mechanisms. Although neighborhood rough set (NRS) has been applied to discover important sparse features, it has hardly ever been utilized in neuroimaging-based biomarker identification, probably due to the inadequate feature evaluation metric and incomplete information provided under a single-granularity. Here, we propose a new NRS-based feature selection method and successfully identify brain functional connectivity biomarkers of schizophrenia (SZ) using functional magnetic resonance imaging (fMRI) data. Specifically, we develop a new weighted metric based on NRS combined with information entropy to evaluate the capacity of features in distinguishing different groups. Inspired by multi-granularity information maximization theory, we further take advantage of the complementary information from different neighborhood sizes via a multi-granularity fusion to obtain the most discriminative and stable features. For validation, we compare our method with six popular feature selection methods using three public omics datasets as well as resting-state fMRI data of 393 SZ patients and 429 healthy controls. Results show that our method obtained higher classification accuracies on both omics data (100.0%, 88.6%, and 72.2% for three omics datasets, respectively) and fMRI data (93.9% for main dataset, and 76.3% and 83.8% for two independent datasets, respectively). Moreover, our findings reveal biologically meaningful substrates of SZ, notably involving the connectivity between the thalamus and superior temporal gyrus as well as between the postcentral gyrus and calcarine gyrus. Taken together, we propose a new NRS-based feature selection method that shows the potential of exploring effective and sparse neuroimaging-based biomarkers of mental disorders.

Cognitive control deficits are associated with impaired executive functioning in schizophrenia. The Dual Mechanisms of Control framework suggests that proactive control requires sustained dorsolateral prefrontal activity, whereas reactive control marshals a larger network. However, primate studies suggest these processes are maintained by dual-encoding regions. To distinguish between these theories, we compared the distinctiveness of proactive and reactive control functional neuroanatomy. In a reanalysis of data from a previous study, 47 adults with schizophrenia and 56 controls completed the Dot Pattern Expectancy task during an fMRI scan examining proactive and reactive control in frontoparietal and medial temporal regions. Areas suggesting specialized control or between-group differences were tested for association with symptoms and task performance. Elastic net models additionally explored these areas' predictive abilities regarding performance. Most regions were active in both reactive and proactive control. However, evidence of specialized proactive control was found in the left middle and superior frontal gyri. Control participants showed greater proactive control in the left middle and right inferior frontal gyri. Elastic net models moderately predicted task performance and implicated various frontal gyri regions in control participants, with additional involvement of anterior cingulate and posterior parietal regions for reactive control. Elastic nets for patient participants implicated the inferior and superior frontal gyri, and posterior parietal lobe. Specialized cognitive control was unassociated with either performance or schizophrenia symptomatology. Future work is needed to clarify the distinctiveness of proactive and reactive control, and its role in executive deficits in severe psychopathology.

ObjectivesThe distinction between bipolar I disorder (BD-I) and bipolar II disorder (BD-II) has been a topic of long-lasting debate. This study examined differences between BD-I and BD-II in a large, global sample of OABD, focusing on general functioning, cognition and somatic burden as these domains are often affected in OABD.MethodsCross-sectional analyses were conducted with data from the Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) database. The sample included 963 participants aged ≥50 years (714 BD-I, 249 BD-II). Sociodemographic and clinical factors were compared between BD subtypes including adjustment for study cohort. Multivariable analyses were conducted with generalized linear mixed models (GLMMs) and estimated associations between BD subtype and (1) general functioning (GAF), (2) cognitive performance (g-score) and (3) somatic burden, with study cohort as random intercept.ResultsAfter adjustment for study cohort, BD-II patients more often had a late onset ≥50 years (p = 0.008) and more current severe depression (p = 0.041). BD-I patients were more likely to have a history of psychiatric hospitalization (p < 0.001) and current use of anti-psychotics (p = 0.003). Multivariable analyses showed that BD subtype was not related to GAF, cognitive g-score or somatic burden.ConclusionBD-I and BD-II patients did not differ in terms of general functioning, cognitive impairment or somatic burden. Some clinical differences were observed between the groups, which could be the consequence of diagnostic definitions. The distinction between BD-I and BD-II is not the best way to subtype OABD patients. Future research should investigate other disease specifiers in this population.

Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

Brain functional networks identified from resting functional magnetic resonance imaging (fMRI) data have the potential to reveal biomarkers for brain disorders, but studies of complex mental illnesses such as schizophrenia (SZ) often yield mixed results across replication studies. This is likely due in part to the complexity of the disorder, the short data acquisition time, and the limited ability of the approaches for brain imaging data mining. Therefore, the use of analytic approaches which can both capture individual variability while offering comparability across analyses is highly preferred. Fully blind data-driven approaches such as independent component analysis (ICA) are hard to compare across studies, and approaches that use fixed atlas-based regions can have limited sensitivity to individual sensitivity. By contrast, spatially constrained ICA (scICA) provides a hybrid, fully automated solution that can incorporate spatial network priors while also adapting to new subjects. However, scICA has thus far only been used with a single spatial scale (ICA dimensionality, i.e., ICA model order). In this work, we present an approach using multi-objective optimization scICA with reference algorithm (MOO-ICAR) to extract subject-specific intrinsic connectivity networks (ICNs) from fMRI data at multiple spatial scales, which also enables us to study interactions across spatial scales. We evaluate this approach using a large N (N > 1,600) study of schizophrenia divided into separate validation and replication sets. A multi-scale ICN template was estimated and labeled, then used as input into scICA which was computed on an individual subject level. We then performed a subsequent analysis of multiscale functional network connectivity (msFNC) to evaluate the patient data, including group differences and classification. Results showed highly consistent group differences in msFNC in regions including cerebellum, thalamus, and motor/auditory networks. Importantly

Emerging evidence suggests brain white matter alterations in adolescents with early-onset psychosis (EOP; age of onset <18 years). However, as neuroimaging methods vary and sample sizes are modest, results remain inconclusive. Using harmonized data processing protocols and a mega-analytic approach, we compared white matter microstructure in EOP and healthy controls using diffusion tensor imaging (DTI). Our sample included 321 adolescents with EOP (median age = 16.6 years, interquartile range (IQR) = 2.14, 46.4% females) and 265 adolescent healthy controls (median age = 16.2 years, IQR = 2.43, 57.7% females) pooled from nine sites. All sites extracted mean fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) for 25 white matter regions of interest per participant. ComBat harmonization was performed for all DTI measures to adjust for scanner differences. Multiple linear regression models were fitted to investigate case-control differences and associations with clinical variables in regional DTI measures. We found widespread lower FA in EOP compared to healthy controls, with the largest effect sizes in the superior longitudinal fasciculus (Cohen's d = 0.37), posterior corona radiata (d = 0.32), and superior fronto-occipital fasciculus (d = 0.31). We also found widespread higher RD and more localized higher MD and AD. We detected significant effects of diagnostic subgroup, sex, and duration of illness, but not medication status. Using the largest EOP DTI sample to date, our findings suggest a profile of widespread white matter microstructure alterations in adolescents with EOP, most prominently in male individuals with early-onset schizophrenia and individuals with a shorter duration of illness.

Oxytocin (OT) is involved in the regulation of physiological processes and emotional states, with increasing evidence for its beneficial actions being mediated by the autonomic and immune systems. Growing evidence suggests that OT plays a role in the pathophysiology of different psychiatric disorders. Given the limited information in humans the aim of this study was to retrospectively explore plasma OT levels in psychiatric patients, particularly focusing on sex-related differences, as compared with healthy controls. The patients studied here were divided into three groups diagnosed with obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). Plasma OT levels were significantly different between healthy men and women, with the latter showing higher values, while none of the three psychiatric groups showed sex-related differences in the parameters measured here. The intergroup analyses showed that the OT levels were significantly higher in OCD, lower in PTSD and even more reduced in MDD patients than in healthy subjects. These differences were also confirmed when gender was considered, with the exception of PTSD men, in whom OT levels were similar to those of healthy men. The present results indicated that OT levels were higher amongst healthy women than men, while a sex difference was less apparent or reversed in psychiatric patients. Reductions in sex differences in psychopathologies may be related to differential vulnerabilities in processes associated with basic adaptive and social functions.

Depression, one of the most common diseases in older adults, carries significant risk for morbidity and mortality. Because of the burgeoning population of older adults, the enormous burden of late-life depression, and the limited efficacy of current antidepressants in older adults, biologically plausible models that translate into selective depression prevention strategies are needed. Insomnia predicts depression recurrence and is a modifiable target to prevent incident and recurrent depression in older adults. Yet, it is not known how insomnia gets converted into biological- and affective risk for depression, which is critical for identification of molecular targets for pharmacologic interventions, and for refinement of insomnia treatments that target affective responding to improve efficacy. Sleep disturbance activates inflammatory signaling and primes immune responses to subsequent inflammatory challenge. In turn, inflammatory challenge induces depressive symptoms, which correlate with activation of brain regions implicated in depression. This study hypothesizes that insomnia serves as a vulnerability factor for inflammation-related depression; older adults with insomnia will show heightened inflammatory- and affective responding to inflammatory challenge as compared to those without insomnia. To test this hypothesis, this protocol paper describes a placebo-controlled, randomized, double-blind study of low dose endotoxin in older adults (n = 160; 60-80 y) with insomnia vs. comparison controls without insomnia. The aims of this study are to examine differences in depressive symptoms, measures of negative affective responding, and measures of positive affective responding as a function of insomnia and inflammatory challenge. If the hypotheses are confirmed, older adults with two "hits", insomnia and inflammatory activation, would represent a high risk group to be prioritized for monitoring and for depression prevention efforts using treatments that t

IntroductionThe cognitive and psychotic symptoms in patients with schizophrenia (SZ) are thought to result from disrupted brain network connectivity.MethodsWe capitalize on the high spatiotemporal resolution of magnetoencephalography imaging (MEG) to record spontaneous neuronal activity in resting state networks in 21 SZ compared with 21 healthy controls (HC).ResultsWe found that SZ showed significant global disrupted functional connectivity in delta-theta (2-8 Hz), alpha (8-12 Hz), and beta (12-30 Hz) frequencies, compared to HC. Disrupted global connectivity in alpha frequencies with bilateral frontal cortices was associated with more severe clinical psychopathology (i.e., positive psychotic symptoms). Specifically, aberrant connectivity in beta frequencies between the left primary auditory cortex and cerebellum, was linked to greater hallucination severity in SZ. Disrupted connectivity in delta-theta frequencies between the medial frontal and left inferior frontal cortex was associated with impaired cognition.DiscussionThe multivariate techniques employed in the present study highlight the importance of applying our source reconstruction techniques which leverage the high spatial localization abilities of MEG for estimating neural source activity using beamforming methods such as SAM (synthetic aperture morphometry) to reconstruct the source of brain activity, together with functional connectivity assessments, assayed with imaginary coherence metrics, to delineate how neurophysiological dysconnectivity in specific oscillatory frequencies between distinct regions underlie the cognitive and psychotic symptoms in SZ. The present findings employ powerful techniques in spatial and time-frequency domains to provide potential neural biomarkers underlying neuronal network dysconnectivity in SZ that will inform the development of innovations in future neuromodulation treatment development.

IntroductionThe current study aimed to investigate the rates of anxiety, clinical depression, and suicidality and their changes in health professionals during the COVID-19 outbreak.Materials and methodsThe data came from the larger COMET-G study. The study sample includes 12,792 health professionals from 40 countries (62.40% women aged 39.76 ± 11.70; 36.81% men aged 35.91 ± 11.00 and 0.78% non-binary gender aged 35.15 ± 13.03). Distress and clinical depression were identified with the use of a previously developed cut-off and algorithm, respectively.Statistical analysisDescriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses, and Factorial Analysis of Variance (ANOVA) tested relations among variables.ResultsClinical depression was detected in 13.16% with male doctors and 'non-binary genders' having the lowest rates (7.89 and 5.88% respectively) and 'non-binary gender' nurses and administrative staff had the highest (37.50%); distress was present in 15.19%. A significant percentage reported a deterioration in mental state, family dynamics, and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (24.64% vs. 9.62%; p < 0.0001). Suicidal tendencies were at least doubled in terms of RASS scores. Approximately one-third of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop clinical depression was associated with a history of Bipolar disorder (RR = 4.23).ConclusionsThe current study reported findings in health care professionals similar in magnitude and quality to those reported earlier in the general population although rates of clinical depression, suicidal tendencies, and adherence to conspiracy theories were much lower. However, the general model of factors interplay seems to be the same and this could be of practical utility since many of these factors are modifiable.

BackgroundIncreased expression of the complement component 4A (C4A) gene is associated with a greater lifetime risk of schizophrenia. In the brain, C4A is involved in synaptic pruning; yet, it remains unclear the extent to which upregulation of C4A alters brain development or is associated with the risk for psychotic symptoms in childhood. Here, we perform a multi-ancestry phenome-wide association study in 7789 children aged 9-12 years to examine the relationship between genetically regulated expression (GREx) of C4A, childhood brain structure, cognition, and psychiatric symptoms.ResultsWhile C4A GREx is not related to childhood psychotic experiences, cognition, or global measures of brain structure, it is associated with a localized reduction in regional surface area (SA) of the entorhinal cortex. Furthermore, we show that reduced entorhinal cortex SA at 9-10 years predicts a greater number and severity of psychosis-like events at 1-year and 2-year follow-up time points. We also demonstrate that the effects of C4A on the entorhinal cortex are independent of genome-wide polygenic risk for schizophrenia.ConclusionsOur results suggest neurodevelopmental effects of C4A on childhood medial temporal lobe structure, which may serve as a biomarker for schizophrenia risk prior to symptom onset.

Understanding patient responsiveness, a component of fidelity, is essential as it impacts treatment outcome and ongoing use of treatment elements. This study evaluated patient responsiveness-operationalized as receptivity to treatment modules and ratings of the usefulness and the utilization of treatment elements-to the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) in a sample of adults with serious mental illness (SMI) and sleep/circadian dysfunction. Adults with SMI and sleep/circadian dysfunction (N = 104) received TranS-C in a community mental health setting. Independent raters rated TranS-C sessions to assess receptivity. At posttreatment and 6-month follow-up, participants completed a usefulness scale, utilization scale, the PROMIS Sleep Disturbance (PROMIS-SD) and Sleep-Related Impairment (PROMIS-SRI) scales, DSM-5 Cross-Cutting Measure (DSM-5-CC), and Sheehan Disability Scale (SDS). Receptivity was rated as somewhat to fully understood, and predicted a reduction on the DSM-5-CC. On average, participants rated TranS-C as moderately useful and utilized treatment elements occasionally. Ratings of usefulness were associated with the PROMIS-SD, PROMIS-SRI, and DSM-5-CC at posttreatment, but not with the SDS. Ratings of utilization were not associated with outcome. The findings add to the literature on patient responsiveness, an implementation outcome, and provide data on the utility of TranS-C within a community mental health setting.

BackgroundWe examined whether digital phenotyping of spontaneous speech, such as the use of specific word categories during speech samples, was associated with depressive symptoms in youth who were at familial and clinical risk for mood disorders.MethodsParticipants (ages 13-19) had active mood symptoms, mood instability, and at least one parent with bipolar or major depressive disorder. During a randomized trial of family-focused therapy, participants were instructed to make weekly calls to a central voice server and leave speech samples in response to automated prompts. We coded youths' speech samples with the Linguistic Inquiry and Word Count system and used machine learning to identify the combination of speech features that were most closely associated with the course of depressive symptoms over 18 weeks.ResultsA total of 253 speech samples were collected from 44 adolescents (mean age = 15.8 years; SD = 1.6) over 18 weeks. Speech containing affective processes, social processes, drives toward risk or reward, nonfluencies, and time orientation words were correlated with depressive symptoms at concurrent time periods (ps < 0.01). Machine learning analyses revealed that affective processes, nonfluencies, drives and risk words combined to most strongly predict changes in depressive symptoms over 18 weeks of treatment.LimitationsStudy results were limited by the small sample and the exclusion of paralinguistic or contextual variables in analyzing speech samples.ConclusionsIn youth at high risk for mood disorders, knowledge of speech patterns may inform prognoses during outpatient psychosocial treatment.

BackgroundResearch on the precursors of borderline personality disorder (BPD) reveals numerous child and adolescent risk factors, with impulsivity and trauma among the most salient. Yet few prospective longitudinal studies have examined pathways to BPD, particularly with inclusion of multiple risk domains.MethodsWe examined theory-informed predictors of young-adult BPD (a) diagnosis and (b) dimensional features from childhood and late adolescence via a diverse (47% non-white) sample of females with (n = 140) and without (n = 88) carefully diagnosed childhood attention-deficit hyperactivity disorder (ADHD).ResultsAfter adjustment for key covariates, low levels of objectively measured executive functioning in childhood predicted young adult BPD diagnostic status, as did a cumulative history of childhood adverse experiences/trauma. Additionally, both childhood hyperactivity/impulsivity and childhood adverse experiences/trauma predicted young adult BPD dimensional features. Regarding late-adolescent predictors, no significant predictors emerged regarding BPD diagnosis, but internalizing and externalizing symptoms were each significant predictors of BPD dimensional features. Exploratory moderator analyses revealed that predictions to BPD dimensional features from low executive functioning were heightened in the presence of low socioeconomic status.ConclusionsGiven our sample size, caution is needed when drawing implications. Possible future directions include focus on preventive interventions in populations with enhanced risk for BPD, particularly those focused on improving executive functioning skills and reducing risk for trauma (and its manifestations). Replication is required, as are sensitive measures of early emotional invalidation and extensions to male samples.

Purpose of reviewAddressing cardiometabolic risk factors in persons with serious mental illness requires early screening and proactive medical management in both medical and mental health settings.Recent findingsCardiovascular disease remains the leading cause of death for persons with serious mental illness (SMI), such as schizophrenia or bipolar disorder, much of which is driven by a high prevalence of metabolic syndrome, diabetes, and tobacco use. We summarize barriers and recent approaches to screening and treatment for metabolic cardiovascular risk factors within physical health and specialty mental health settings. Incorporating system-based and provider-level support within physical health and psychiatric clinical settings should contribute to improvement for screening, diagnosis, and treatment for cardiometabolic conditions for patients with SMI. Targeted education for clinicians and leveraging multi-disciplinary teams are important first steps to recognize and treat populations with SMI at risk of CVD.

BackgroundSexual minority adolescents and young adults are at higher risk of eating disorders compared to heterosexual peers. However, little is known about the clinical and psychiatric presentation of this population requiring inpatient medical stabilization. Given the increased risk for eating disorder behaviors in sexual minority individuals amidst increased rates of medical hospitalizations secondary to eating disorders, it is important to understand presenting characteristics of this population. The objectives of this study were to (1) describe the clinical characteristics of sexual minority adolescents and young adults with eating disorders admitted for medical instability and (2) compare psychiatric co-morbidities and suicidality of sexual minority adolescents and young adults to heterosexual peers.MethodsA retrospective chart review was conducted of 601 patients admitted to a large inpatient eating disorders medical stabilization unit between 2012 and 2020. Data collected included demographics, medical data including vital signs, and psychiatric characteristics. Chi square or t-tests were used to examine potential differences in clinical characteristics and psychiatric co-morbidities between groups. Modified Poisson regression was used to assess associations between sexual orientation and psychiatric co-morbidities.ResultsOver one fifth (21.1%, n = 103) of our inpatient sample identified as a sexual minority individual. The average age of participants was 15.6 years (2.7). Sexual minority adolescents and young adults had higher percent median body mass index compared to heterosexual peers and yet equally severe vital sign instability on admission. Sexual minority adolescents and young adults were almost 1.5 times more likely to have a psychiatric comorbidity with higher rates of depression, anxiety, and post-traumatic stress disorder. Sexual minority adolescents and young adults were approximately two times more likely to have a history of self-injuriou

BackgroundSerious mental illness (SMI) can have devastating consequences. Unfortunately, many patients with SMI do not receive evidence-based psychological treatment (EBPTs) in routine practice settings. One barrier is poor "fit" between EBPTs and contexts in which they are implemented. The present study will evaluate implementation and effectiveness outcomes of the Transdiagnostic Intervention for Sleep and Circadian Dysfunction (TranS-C) implemented in community mental health centers (CMHCs). TranS-C was designed to target a range of SMI diagnoses by addressing a probable mechanism and predictor of SMI: sleep and circadian problems. We will investigate whether adapting TranS-C to fit CMHC contexts improves providers' perceptions of fit and patient outcomes.MethodsTranS-C will be implemented in at least ten counties in California, USA (N = 96 providers; N = 576 clients), via facilitation. CMHC sites are cluster-randomized by county to Adapted TranS-C or Standard TranS-C. Within each county, patients are randomized to immediate TranS-C or usual care followed by delayed treatment with TranS-C (UC-DT). Aim 1 will compare TranS-C (combined Adapted and Standard) with UC-DT on improvements in sleep and circadian problems, functional impairment, and psychiatric symptoms. Sleep and circadian problems will also be tested as a mediator between treatment condition (combined TranS-C versus UC-DT) and functional impairment/psychiatric symptoms. Aim 2 will evaluate whether Adapted TranS-C is superior to Standard TranS-C with respect to provider perceptions of fit. Aim 3 will evaluate whether the relation between TranS-C treatment condition (Adapted versus Standard) and patient outcomes is mediated by better provider perceptions of fit in the Adapted condition. Exploratory analyses will (1) compare Adapted versus Standard TranS-C on patient perceptions of credibility/improvement and select PhenX Toolkit outcomes and (2) evaluate possible moderators.DiscussionThis trial has the po

RNA editing, the endogenous modification of nucleic acids, is known to be altered in genes with important neurological function in schizophrenia (SCZ). However, the global profile and molecular functions of disease-associated RNA editing remain unclear. Here, we analyzed RNA editing in postmortem brains of four SCZ cohorts and uncovered a significant and reproducible trend of hypoediting in patients of European descent. We report a set of SCZ-associated editing sites via WGCNA analysis, shared across cohorts. Using massively parallel reporter assays and bioinformatic analyses, we observed that differential 3' untranslated region (3'UTR) editing sites affecting host gene expression were enriched for mitochondrial processes. Furthermore, we characterized the impact of two recoding sites in the mitofusin 1 (MFN1) gene and showed their functional relevance to mitochondrial fusion and cellular apoptosis. Our study reveals a global reduction of editing in SCZ and a compelling link between editing and mitochondrial function in the disease.