Anti-spike antibody responses to SARS-CoV-2 mRNA vaccines in people with schizophrenia and schizoaffective disorder.

Importance: Individuals with schizophrenia are at higher risk for severe COVID-19 illness and severe breakthrough infection following vaccination. It is unclear whether immune response to vaccination differs in this population. Objective: To assess whether anti-SARS-CoV-2 spike antibody titers after vaccination differ in people with a diagnosis of schizophrenia or schizoaffective disorder (SZ) compared to controls without a psychiatric disorder. Design: This cohort study assessed antibody response following the first and second dose of mRNA vaccines at longitudinal timepoints, up to 7 weeks following the first dose of vaccine. Setting: A multi-center study including psychiatric healthcare settings in the United States and Europe. Participants: 205 adults with no history of COVID-19 infection, including 106 individuals with SZ and 99 controls without a psychiatric disorder, who received their first dose of SARS-CoV-2 mRNA vaccine between December 20, 2020 and May 27, 2021. Main outcomes and measures: Mean SARS-CoV-2 anti-Spike IgG antibody levels within 7 weeks after the first dose of vaccination. Results: A total of 205 individuals (mean [SD] age, 44.7 [12.0] years; 90 [43.9%] male) were included, of which 106 (51.7%) were diagnosed with SZ. SZ was associated with lower mean log antibody levels (-0.15; 95% CI, -0.27 to -0.03, P = 0.016) after adjusting for age, sex, body mass index, smoking, days since vaccination, and vaccine manufacturer. In secondary analyses of dose-specific responses, SZ was associated with a lower mean log antibody level after the second dose of vaccine (-0.23; 95% CI -0.39 to -0.06, P = 0.006), but not the first dose of vaccine (0.00; 95% CI -0.18- 0.19, P = 0.96). Conclusions and Relevance: In this cohort study of individuals with SZ and a control group without psychiatric disorders, SZ was associated with lower SARS-CoV-2 anti-spike antibody levels following 2 doses of SARS-CoV-2 mRNA vaccination. This highlights the need for further studies assessing vaccine immunogenicity in individuals with schizophrenia.

Social networks of people with serious mental illness who smoke: potential role in a smoking cessation intervention.

BACKGROUND: Smoking is a major contributor to morbidity and mortality among individuals with serious mental illness (SMI) and social networks may play an important role in smoking behaviors. AIMS: Our objectives were to (1) describe the network characteristics of adults with SMI who smoke tobacco (2) explore whether network attributes were associated with nicotine dependence. METHODS: We performed a secondary analysis of baseline data from a tobacco smoking cessation intervention trial among 192 participants with SMI. A subgroup (n = 75) completed questions on the characteristics of their social network members. The network characteristics included network composition (e.g. proportion who smoke) and network structure (e.g. density of connections between members). We used multilevel models to examine associations with nicotine dependence. RESULTS: Participant characteristics included: a mean age 50 years, 49% women, 48% Black, and 41% primary diagnosis of schizophrenia/schizoaffective disorder. The median personal network proportion of active smokers was 22%, active quitters 0%, and non-smokers 53%. The density of ties between actively smoking network members was greater than between non-smoking members (55% vs 43%, p = .02). Proportion of network smokers was not associated with nicotine dependence. CONCLUSIONS: We identified potential social network challenges and assets to smoking cessation and implications for network interventions among individuals with SMI.

Tobacco smoking and nicotine vaping in persons with first episode psychosis.

Tobacco smoking is highly prevalent in persons with psychosis and is the leading cause of preventable mortality in this population. Less is known about tobacco smoking in persons with first episode psychosis (FEP) and there have been no estimates about the prevalence of nicotine vaping in FEP. This study reports rates of tobacco smoking and nicotine vaping in young people with FEP enrolled in Coordinated Specialty Care programs in Pennsylvania and Maryland. Using data collected from 2021 to 2023, we examined lifetime and recent smoking and vaping and compared smokers and vapers to nonusers on symptoms, functioning, and substance use. The sample included 445 participants aged 13-35 with recent psychosis onset. Assessments were collected by program staff. Overall, 28 % of participants engaged in either smoking or vaping within 30 days of the admission assessment. Smokers and vapers were disproportionately male, cannabis users, and had lower negative symptom severity than non-smokers. Vapers had higher role and social functioning. Both smoking and vaping were related to a longer time from psychosis onset to program enrollment. We compare these findings to previous studies and suggest steps for addressing smoking and vaping in this vulnerable population.

Levels of Matrix Metalloproteinase 9 Are Elevated in Persons With Schizophrenia or Bipolar Disorder: The Role of Modifiable Factors.

Background: Matrix metalloproteinases (MMPs) are a diverse set of enzymes associated with inflammation. MMP-9 is of particular interest because it has been associated with autoimmune and cardiopulmonary disorders, tobacco smoking, and obesity, prevalent in psychiatric populations. Methods: Sensitive enzyme immunoassays measured MMP-9 in blood samples from 1121 individuals (mean age = 35.6 [SD = 13.0] years; 47.7% male; 440 with schizophrenia, 399 with bipolar disorder, and 282 without a psychiatric disorder). We estimated the odds of diagnosis associated with MMP-9, demographic variables, tobacco smoking, and obesity, and also the partial explained variance using regression methods. We also determined the association between psychiatric medications and MMP-9 levels. Results: Individuals with elevated MMP-9 levels had higher odds of schizophrenia or bipolar disorder compared with the nonpsychiatric group adjusted for demographic variables. Partial correlation analyses indicated the demographic-adjusted variance associated with MMP-9, smoking, obesity, and their interaction explained 59.6% for schizophrenia and 39.9% for bipolar disorder. Levels of MMP-9 were substantially lower in individuals receiving valproate, particularly relatively high doses. Conclusions: Individuals with higher levels of MMP-9 have significantly higher odds of schizophrenia or bipolar disorder. Individuals receiving valproate had substantially lower levels of MMP-9, possibly related to its ability to inhibit histone deacetylation. A substantial portion of the variance in clinical disorders associated with MMP-9 can be attributed to smoking or obesity. Interventions to reduce smoking and obesity might reduce the morbidity and mortality associated with elevated MMP-9 levels and improve the health outcomes of individuals with these disorders.

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker.

Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system-derived neuroinflammation, synapse pruning, and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced, or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal, inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n = 335) and/or in nonpsychiatric comparison subjects (NCs; n = 233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-reactive protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F = 20.74, p < 0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants, plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff = 0.39, CI = 0.01-0.77, R2 = 0.18, p < 0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index, race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR-NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F = 5.16, p < 0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 requires replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia.

Effect of a Tobacco Cessation Intervention Incorporating Weight Management for Adults With Serious Mental Illness: A Randomized Clinical Trial.

Importance: Tobacco smoking drives markedly elevated cardiovascular disease risk and preventable death in persons with serious mental illness, and these risks are compounded by the high prevalence of overweight/obesity that smoking cessation can exacerbate. Guideline-concordant combined pharmacotherapy and behavioral smoking cessation treatment improves abstinence but is not routinely offered in community settings, particularly to those not seeking to quit smoking immediately. Objective: To determine the effectiveness of an 18-month pharmacotherapy and behavioral smoking cessation intervention incorporating weight management and support for physical activity in adults with serious mental illness interested in quitting smoking within 1 or 6 months. Design, Setting, and Participants: This was a randomized clinical trial conducted from July 25, 2016, to March 20, 2020, at 4 community health programs. Adults with serious mental illness who smoked tobacco daily were included in the study. Participants were randomly assigned to intervention or control, stratified by willingness to try to quit immediately (within 1 month) or within 6 months. Assessors were masked to group assignment. Interventions: Pharmacotherapy, primarily varenicline, dual-form nicotine replacement, or their combination; tailored individual and group counseling for motivational enhancement; smoking cessation and relapse prevention; weight management counseling; and support for physical activity. Controls received quitline referrals. Main Outcome and Measures: The primary outcome was biochemically validated, 7-day point-prevalence tobacco abstinence at 18 months. Results: Of the 298 individuals screened for study inclusion, 192 enrolled (mean [SD] age, 49.6 [11.7] years; 97 women [50.5%]) and were randomly assigned to intervention (97 [50.5%]) or control (95 [49.5%]) groups. Participants self-identified with the following race and ethnicity categories: 93 Black or African American (48.4%), 6 Hispanic or Latino (3.1%), 90 White (46.9%), and 9 other (4.7%). A total of 82 participants (42.7%) had a schizophrenia spectrum disorder, 62 (32.3%) had bipolar disorder, and 48 (25.0%) had major depressive disorder; 119 participants (62%) reported interest in quitting immediately (within 1 month). Primary outcome data were collected in 183 participants (95.3%). At 18 months, 26.4% of participants (observed count, 27 of 97 [27.8%]) in the intervention group and 5.7% of participants (observed count, 6 of 95 [6.3%]) in the control group achieved abstinence (adjusted odds ratio [OR], 5.9; 95% CI, 2.3-15.4; P < .001). Readiness to quit within 1 month did not statistically significantly modify the intervention's effect on abstinence. The intervention group did not have significantly greater weight gain than the control group (mean weight change difference, 1.6 kg; 95% CI, -1.5 to 4.7 kg). Conclusions and Relevance: Findings of this randomized clinical trial showed that in persons with serious mental illness who are interested in quitting smoking within 6 months, an 18-month intervention with first-line pharmacotherapy and tailored behavioral support for smoking cessation and weight management increased tobacco abstinence without significant weight gain. Trial Registration: ClinicalTrials.gov Identifier: NCT02424188.

Promoting Evidence-Based Tobacco Cessation Treatment in Community Mental Health Clinics: Protocol for a Prepost Intervention Study.

BACKGROUND: Tobacco smoking is highly prevalent among persons with serious mental illness (SMI) and is the largest contributor to premature mortality in this population. Evidence-based smoking cessation therapy with medications and behavioral counseling is effective for persons with SMI, but few receive this treatment. Mental health providers have extensive experience working with clients with SMI and frequent treatment contacts, making them well positioned to deliver smoking cessation treatment. However, few mental health providers feel adequately trained to deliver this treatment, and many providers believe that smokers with SMI are not interested in quitting or have concerns about the safety of smoking cessation pharmacotherapy, despite substantial evidence to the contrary. OBJECTIVE: We present the protocol for the pilot "IMPACT" (Implementing Action for Tobacco Smoking Cessation Treatment) study, which aims to pilot test a multicomponent implementation intervention to increase the delivery of evidence-based tobacco smoking cessation treatment in community mental health clinics. METHODS: We are using a prepost observational design to examine the effects of an implementation intervention designed to improve mental health providers' delivery of the following four evidence-based practices related to smoking cessation treatment: (1) assessment of smoking status, (2) assessment of willingness to quit, (3) behavioral counseling, and (4) pharmacotherapy prescribing. To overcome key barriers related to providers' knowledge and self-efficacy of smoking cessation treatment, the study will leverage implementation strategies including (1) real-time and web-based training for mental health providers about evidence-based smoking cessation treatment and motivational interviewing, including an avatar practice module; (2) a tobacco smoking treatment protocol; (3) expert consultation; (4) coaching; and (5) organizational strategy meetings. We will use surveys and in-depth interviews to assess the implementation intervention's effects on providers' knowledge and self-efficacy, the mechanisms of change targeted by the intervention, as well as providers' perceptions of the acceptability, appropriateness, and feasibility of both the evidence-based practices and implementation strategies. We will use data on care delivery to assess providers' implementation of evidence-based smoking cessation practices. RESULTS: The IMPACT study is being conducted at 5 clinic sites. More than 50 providers have been enrolled, exceeding our recruitment target. The study is ongoing. CONCLUSIONS: In order for persons with SMI to realize the benefits of smoking cessation treatment, it is important for clinicians to implement evidence-based practices successfully. This pilot study will result in a set of training modules, implementation tools, and resources for clinicians working in community mental health clinics to address tobacco smoking with their clients. Trial Registration: ClinicalTrials.gov NCT04796961; https://clinicaltrials.gov/ct2/show/NCT04796961. TRIAL REGISTRATION: ClinicalTrials.gov NCT04796961; https://clinicaltrials.gov/ct2/show/NCT04796961. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44787.

Review of Major Social Determinants of Health in Schizophrenia-Spectrum Psychotic Disorders: III. Biology.

BACKGROUND: Social determinants of health (SDoHs) are nonmedical factors that significantly impact health and longevity. We found no published reviews on the biology of SDoHs in schizophrenia-spectrum psychotic disorders (SSPD). STUDY DESIGN: We present an overview of pathophysiological mechanisms and neurobiological processes plausibly involved in the effects of major SDoHs on clinical outcomes in SSPD. STUDY RESULTS: This review of the biology of SDoHs focuses on early-life adversities, poverty, social disconnection, discrimination including racism, migration, disadvantaged neighborhoods, and food insecurity. These factors interact with psychological and biological factors to increase the risk and worsen the course and prognosis of schizophrenia. Published studies on the topic are limited by cross-sectional design, variable clinical and biomarker assessments, heterogeneous methods, and a lack of control for confounding variables. Drawing on preclinical and clinical studies, we propose a biological framework to consider the likely pathogenesis. Putative systemic pathophysiological processes include epigenetics, allostatic load, accelerated aging with inflammation (inflammaging), and the microbiome. These processes affect neural structures, brain function, neurochemistry, and neuroplasticity, impacting the development of psychosis, quality of life, cognitive impairment, physical comorbidities, and premature mortality. Our model provides a framework for research that could lead to developing specific strategies for prevention and treatment of the risk factors and biological processes, thereby improving the quality of life and increasing the longevity of people with SSPD. CONCLUSIONS: Biology of SDoHs in SSPD is an exciting area of research that points to innovative multidisciplinary team science for improving the course and prognosis of these serious psychiatric disorders.

Designing Practical Motivational Interviewing Training for Mental Health Practitioners Implementing Behavioral Lifestyle Interventions: Protocol for 3 Pilot Intervention Studies.

BACKGROUND: Motivational interviewing (MI) is an evidence-based, patient-centered communication method shown to be effective in helping persons with serious mental illness (SMI) to improve health behaviors. In clinical trials where study staff conducted lifestyle interventions incorporating an MI approach, cardiovascular disease (CVD) risk profiles of participants with SMI showed improvement. Given the disproportionate burden of CVD in this population, practitioners who provide somatic and mental health care to persons with SMI are ideally positioned to deliver patient-centered CVD risk reduction interventions. However, the time for MI training (traditionally 16-24 hours), follow-up feedback, and the coaching required to develop and maintain patient-centered skills are significant barriers to incorporating MI when scaling up these evidence-based practices. OBJECTIVE: We describe the design and development of the following 2 scalable MI training approaches for community mental health practitioners: real-time brief workshops and follow-up asynchronous avatar training. These approaches are being used in 3 different pilot implementation research projects that address weight loss, smoking cessation, and CVD risk reduction in people with SMI who are a part of ALACRITY Center, a research-to-practice translation center funded by the National Institute of Mental Health. METHODS: Clinicians and staff in community mental health clinics across Maryland were trained to deliver 3 distinct evidence-based physical health lifestyle interventions using an MI approach to persons with SMI. The real-time brief MI workshop training for ACHIEVE-D weight loss coaches was 4 hours; IMPACT smoking cessation counselors received 2-hour workshops and prescribers received 1-hour workshops; and RHYTHM CVD risk reduction program staff received 4 hours of MI. All workshop trainings occurred over videoconference. The asynchronous avatar training includes 1 common didactic instructional module for the 3 projects and 1 conversation simulation unique to each study's target behavior. Avatar training is accessible on a commercial website. We plan to assess practitioners' attitudes and beliefs about MI and evaluate the impact of the 2 MI training approaches on their MI skills 3, 6, and 12 months after training using the MI Treatment Integrity 4.2.1 coding tool and the data generated by the avatar-automated scoring system. RESULTS: The ALACRITY Center was funded in August 2018. We have implemented the MI training for 126 practitioners who are currently delivering the 3 implementation projects. We expect the studies to be complete in May 2023. CONCLUSIONS: This study will contribute to knowledge about the effect of brief real-time training augmented with avatar skills practice on clinician MI skills. If MI Treatment Integrity scoring shows it to be effective, brief videoconference trainings supplemented with avatar skills practice could be used to train busy community mental health practitioners to use an MI approach when implementing physical health interventions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/44830.

Cigarette smoking is associated with Herpesviruses in persons with and without serious mental illness.

INTRODUCTION: Herpesviruses are recognized as major causes of human diseases. Following initial infection, Herpesviruses can undergo cycles of reactivation controlled largely by the immune system. Cigarette smoking is an important modulator of the immune system particularly in individuals with serious mental illness where smoking is associated with increased rates of cardiopulmonary diseases and mortality. However, the effect of smoking on Herpesviruses has not been extensively studied. METHODS: In this nested cohort study, cigarette smoking was assessed in 1323 persons with serious mental illness or without a psychiatric disorder ascertained in a psychiatric health care system and the adjacent community. Participants provided a blood sample from which were measured IgG class antibodies to five human Herpesviruses: Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Herpes Simplex Virus-Type 1 (HSV-1); Varicella Zoster Virus (VZV); and Human Herpes Virus-Type 6 (HHV-6). The associations between smoking variables and antibody levels to the Herpesviruses were analyzed among diagnostic groups in multiple regression models adjusted for age, sex, and race. RESULTS: Current smoking was significantly associated with higher levels of antibodies to CMV (coefficient .183, 95% CI .049, .317, p<.001, q<.007) and the three EBV proteins (EBV NA -(coefficient .088, 95% CI .032, .143, p = .002, q<.014; EBV Virion - coefficient .100, 95% CI .037, .163, p = .002, q<.014; and EBV VCA - coefficient .119, 95% CI .061, .177, p = .00004, q<.0016). The amount of cigarettes smoked was also correlated with higher levels of antibodies to the three EBV proteins. Interaction analyses indicated that the association between cigarette smoking and levels of antibodies to CMV and EBV was independent of diagnostic group. Cigarette smoking was not significantly associated with the level of antibodies to HSV-1, VZV, or HHV-6. CONCLUSIONS: Individuals who smoke cigarettes have increased levels of IgG antibodies to CMV and EBV. Cigarette smoking may be a contributory factor in the relationship between CMV, EBV and chronic somatic disorders associated with these viruses.

The Microbiome and Mental Health Across the Lifespan.

INTRODUCTION: The combined genetic material of the microorganisms in the human body, known as the microbiome, is being increasingly recognized as a major determinant of human health and disease. Although located predominantly on mucosal surfaces, these microorganisms have profound effects on brain functioning through the gut-brain axis. METHOD: The content of the chapter is based on a study group session at the annual meeting of the American College of Neuropsychopharmacology (ACNP). The objective was to discuss the emerging relationship between the human microbiome and mental health as relevant to ACNP's interests in developing and evaluating novel neuropsychiatric treatment strategies. The focus is on specific brain disorders, such as schizophrenia, substance use, and Alzheimer's disease, as well as on broader clinical issues such as suicidality, loneliness and wisdom in old age, and longevity. RESULTS: Studies of schizophrenia indicate that the microbiome of individuals with this disorder differs from that of non-psychiatric comparison groups in terms of diversity and composition. Differences are also found in microbial metabolic pathways. An early study in substance use disorders found that individuals with this disorder have lower levels of beta diversity in their oral microbiome than a comparison group. This measure, along with others, was used to distinguish individuals with substance use disorders from controls. In terms of suicidality, there is preliminary evidence that persons who have made a suicide attempt differ from psychiatric and non-psychiatric comparison groups in measures of beta diversity. Exploratory studies in Alzheimer's disease indicate that gut microbes may contribute to disease pathogenesis by regulating innate immunity and neuroinflammation and thus influencing brain function. In another study looking at the microbiome in older adults, positive associations were found between wisdom and alpha diversity and negative associations with subjective loneliness. In other studies of older adults, here with a focus on longevity, individuals with healthy aging and unusually long lives had an abundance of specific microorganisms which distinguished them from other individuals. DISCUSSION: Future studies would benefit from standardizing methods of sample collection, processing, and analysis. There is also a need for the standardized collection of relevant demographic and clinical data, including diet, medications, cigarette smoking, and other potentially confounding factors. While still in its infancy, research to date indicates a role for the microbiome in mental health disorders and conditions. Interventions are available which can modulate the microbiome and lead to clinical improvements. These include microbiome-altering medications as well as probiotic microorganisms capable of modulating the inflammation in the brain through the gut-brain axis. This research holds great promise in terms of developing new methods for the prevention and treatment of a range of human brain disorders.

Non-SARS Coronaviruses in Individuals with Psychiatric Disorders.

BACKGROUND: The pandemic caused by severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2) has highlighted the importance of coronaviruses in human health. Several seasonal, non-SARS Coronaviruses are endemic in most areas of the world. In a previous study, we found that the level of antibodies to these seasonal Coronaviruses was elevated in persons with a recent onset of psychosis. In the current study, the level of antibodies to seasonal Coronaviruses was compared between individuals with psychiatric disorders and a non-psychiatric comparison group. METHODS: Participants (N = 195) were persons with a diagnosis of schizophrenia, bipolar disorder, major depressive disorder, or without a psychiatric disorder. Each participant had a blood sample drawn from which were measured IgG antibodies to the spike proteins in four non-SARS Coronaviruses, 229E, HKU1, NL63, and OC43, using a multiplex electrochemiluminescence assay. Linear regression models were employed to compare the levels of antibodies between each psychiatric group and the comparison group adjusting for demographic variables. Logistic regression models were employed to calculate the odds ratios associated with increased levels of antibodies to each seasonal Coronavirus based on the 50th percentile level of the comparison group. RESULTS: The schizophrenia group had significantly increased levels of antibodies to the seasonal Coronaviruses OC43 and NL63. This group also had increased odds of having elevated antibody levels to OC43. The major depression group showed a significantly lower level of antibodies to Coronavirus 229E. There were no significant differences between any of the psychiatric groups and the comparison group in the levels of antibodies to seasonal Coronaviruses 229E or HKU1. CONCLUSIONS: The elevated level of antibodies to OC43 and NL63 in the schizophrenia group indicates increased exposure to these agents and raises the possibility that Coronaviruses may contribute to the etiopathology of this disorder. The cause-and-effect relationship between seasonal Coronaviruses and psychiatric disorders should be the subject of additional investigations focusing on longitudinal cohort studies.

Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia.

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD's polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Scaling Evidence-Based Interventions to Improve the Cardiovascular Health of People With Serious Mental Illness.

People with serious mental illnesses (SMIs) experience excess mortality, driven in large part by high rates of cardiovascular disease (CVD), with all cardiovascular disease risk factors elevated. Interventions designed to improve the cardiovascular health of people with SMI have been shown to lead to clinically significant improvements in clinical trials; however, the uptake of these interventions into real-life clinical settings remains limited. Implementation strategies, which constitute the "how to" component of changing healthcare practice, are critical to supporting the scale-up of evidence-based interventions that can improve the cardiovascular health of people with SMI. And yet, implementation strategies are often poorly described and rarely justified theoretically in the literature, limiting the ability of researchers and practitioners to tease apart why, what, how, and when implementation strategies lead to improvement. In this Perspective, we describe the implementation strategies that the Johns Hopkins ALACRITY Center for Health and Longevity in Mental Illness is using to scale-up three evidenced-based interventions related to: (1) weight loss; (2) tobacco smoking cessation treatment; and (3) hypertension, dyslipidemia, and diabetes care for people with SMI. Building on concepts from the literature on complex health interventions, we focus on considerations related to the core function of an intervention (i.e., or basic purposes of the change process that the health intervention seeks to facilitate) vs. the form (i.e., implementation strategies or specific activities taken to carry out core functions that are customized to local contexts). By clearly delineating how implementation strategies are operationalized to support the interventions' core functions across these three studies, we aim to build and improve the future evidence base of how to adapt, implement, and evaluate interventions to improve the cardiovascular health of people with SMI.

Impacts of Neighborhood Characteristics and Surgical Treatment Disparities on Overall Mortality in Stage I Renal Cell Carcinoma Patients.

Racial/ethnic minority groups in the United States have high renal cell carcinoma (RCC) mortality rates. This study assessed surgical treatment disparities across racial/ethnic groups and impacts of neighborhood socioeconomic characteristics on surgical treatments and overall mortality. Stage I RCC patients diagnosed between 2004 and 2016 from National Cancer Database were included (n = 238,141). We assessed differences in associations between race/ethnicity and treatment patterns using logistic regression and between race/ethnicity and overall mortality using Cox regression with and without neighborhood characteristics in the regression models. When compared to non-Hispanic Whites (NHWs), American Indians/Alaska Natives and non-Hispanic Blacks (NHBs) were more likely not to receive surgical care and all racial/ethnic minority groups had significantly increased odds of undergoing radical rather than partial nephrectomy, even after adjusting for neighborhood characteristics. Including surgical treatment and neighborhood factors in the models slightly attenuated the association, but NHBs had a significantly increased risk of overall mortality. NHBs who underwent radical nephrectomy had an increased risk of mortality (HR 1.15, 95% CI: 1.08-1.23), but not for NHBs who underwent partial nephrectomy (HR 0.92, 95% CI: 0.84-1.02). Neighborhood factors were associated with surgical treatment patterns and overall mortality in both NHBs and NHWs. Neighborhood socioeconomic factors may only partly explain RCC disparities.

Physical Activity Levels and Screen Time among Youth with Overweight/Obesity Using Mental Health Services.

Youth with mental illness have higher levels of obesity than children in the general population. Both regular physical activity and limited screen time have been recommended to reduce and prevent childhood obesity. This study examines accelerometer-based moderate-vigorous physical activity (MVPA) and screen time among youth with overweight/obesity issues who are receiving mental health care. This study looked at a 12-month weight management randomized clinical trial for overweight/obese youth aged 8-18 years who are receiving mental health services. At baseline, MVPA was assessed using accelerometers, and screen time was self-reported. Among 100 youth, 43% were female, 44% were Black, and 48% were <13 years old. In an adjusted general linear model, higher levels of MVPA were associated with the younger age group (p = 0.012), male participants (p = 0.013), and lower BMI z-scores (p = 0.014). In a separate model, higher screen time was associated with participants who were Black (p = 0.007). Achieving optimal cardiovascular health at the population level requires an understanding of the groups that are most in need of additional assistance. These data reinforce that targeted lifestyle approaches to promote increased physical activity and decreased screen time among overweight/obese youth using mental health services may need additional tailoring for sex, age, and race subgroups.

Experiences of Persons With Serious Mental Illness During the COVID-19 Pandemic.

OBJECTIVE: This study aimed to characterize the experiences of persons with serious mental illness during the COVID-19 pandemic. METHODS: Adults with schizophrenia, bipolar disorder, major depression, or no psychiatric disorder (N=195) were interviewed between July 2020 and January 2021. All were previously enrolled in a cohort study. The interviews focused on mental distress and suicidal thoughts, the impact of the pandemic and pandemic-related worries, tobacco and alcohol use, and access to care. Responses of persons with serious mental illness were compared with responses of those without a psychiatric disorder by using multivariate ordered logistic regression analyses. For a subset of participants, responses about suicidal ideation were compared with their responses prior to the pandemic. RESULTS: Compared with participants with no psychiatric disorder, individuals with schizophrenia were more likely to endorse that they felt overwhelmed or anxious, had difficulty concentrating, or were concerned about medical bills and having enough food; they also reported significantly increased tobacco smoking. Individuals with bipolar disorder also reported more COVID-19-related worries than did participants without a psychiatric disorder. Overall, those with a psychiatric disorder reported more frequent mental distress and more recent missed medical visits and medications than did those with no psychiatric disorder. However, participants with serious mental illness did not report a higher rate of suicidal thoughts compared with their prepandemic responses. CONCLUSIONS: The pandemic poses significant challenges to individuals with serious mental illness in terms of COVID-19-related distress. Psychiatric services should proactively address the emotional distress and worries associated with the pandemic.

Agent-Based Modeling for Implementation Research: An Application to Tobacco Smoking Cessation for Persons with Serious Mental Illness.

BACKGROUND: Implementation researchers have sought ways to use simulations to support the core components of implementation, which typically include assessing the need for change, designing implementation strategies, executing the strategies, and evaluating outcomes. The goal of this paper is to explain how agent-based modeling could fulfill this role. METHODS: We describe agent-based modeling with respect to other simulation methods that have been used in implementation science, using non-technical language that is broadly accessible. We then provide a stepwise procedure for developing agent-based models of implementation processes. We use, as a case study to illustrate the procedure, the implementation of evidence-based smoking cessation practices for persons with serious mental illness (SMI) in community mental health clinics. RESULTS: For our case study, we present descriptions of the motivating research questions, specific models used to answer these questions, and a summary of the insights that can be obtained from the models. In the first example, we use a simple form of agent-based modeling to simulate the observed smoking behaviors of persons with SMI in a recently completed trial (IDEAL, Comprehensive Cardiovascular Risk Reduction Trial in Persons with SMI). In the second example, we illustrate how a more complex agent-based approach that includes interactions between patients, providers and site administrators can be used to provide guidance for an implementation intervention that includes training and organizational strategies. This example is based in part on an ongoing project focused on scaling up evidence-based tobacco smoking cessation practices in community mental health clinics in Maryland. CONCLUSION: In this paper we explain how agent-based models can be used to address implementation science research questions and provide a procedure for setting up simulation models. Through our examples, we show how what-if scenarios can be examined in the implementation process, which are particularly useful in implementation frameworks with adaptive components.