Longitudinal study of insomnia, suicidal ideation, and psychopathology in schizophrenia.

OBJECTIVE: Insomnia is a common comorbidity in schizophrenia. Increasing cross-sectional evidence suggests an association between insomnia and suicidal ideation (SI) and symptom severity in schizophrenia. We investigated longitudinal associations over 3 months between insomnia, suicidal ideation, and symptom severity in a group of patients with chronic schizophrenia. METHOD: We performed a secondary analysis of data from n = 305 participants from the Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy (PROACTIVE) schizophrenia trial using regression models. RESULTS: The prevalence of moderate-to-severe insomnia was 17.7 % at baseline and 13.6 % at 3 months, respectively. The prevalence of SI was 22 % at baseline and 22.5 % at 3 months. After controlling for potential confounders, improved SI from baseline to 3 months was associated with both baseline moderate-to-severe insomnia (OR = 3.81, 95 % CI 1.11-13.12, p = 0.034) and improvement in insomnia (OR = 3.50, 95 % CI 1.23-9.92, p = 0.013). Worsening SI from baseline to 3 months was associated with worsening insomnia (OR = 3.50, 95 % CI 1.23-9.92, p = 0.013), but not baseline insomnia. Improvement in BPRS total score from baseline to 3 months was associated with improvement in insomnia (ß = 0.17, p = 0.029), but not baseline insomnia. CONCLUSION: Insomnia is common in patients with chronic schizophrenia and insomnia showed significant associations with SI and psychopathology. Clinicians should consider insomnia when assessing suicide risk in patients with schizophrenia.

Longitudinal study of inflammation and relapse in schizophrenia.

INTRODUCTION: The clinical course of schizophrenia is often characterized by recurrent relapses. Blood inflammatory markers are altered in acute psychosis, and may be state markers for illness relapse in schizophrenia. Few studies have investigated longitudinal, intra-individual changes in inflammatory markers as a predictor of relapse. In the present study, we explored this association in a relapse prevention trial in patients with schizophrenia. METHODS: We analyzed blood inflammatory markers in 200 subjects, with a mean 11 samples per subject, during the 30 month Preventing Relapse in schizophrenia: Oral Antipsychotics Compared to Injectable: eValuating Efficacy (PROACTIVE) trial. Associations between longitudinal changes in inflammatory markers and relapse were analyzed using a within-subjects design. RESULTS: 70 (35 %) of subjects relapsed during the study period. There were no significant differences in mean inflammatory marker levels based on relapse status (yes/no). Baseline levels of inflammatory markers did not predict incident relapse. Among subjects who relapsed, there was a significant decrease in mean blood IL-6 (n = 38, p = 0.019) and IFN-γ (n = 44, p = 0.012) levels from the visit before the relapse to the visit after relapse. CONCLUSION: Although there was some evidence for inflammation as a potential state marker for acute psychosis, we did not find significant evidence for its utility as a relapse-predictive marker.

The Future of Endowed Chairs in Academic Medicine.

As the landscape of philanthropy changes following the COVID-19 pandemic, this commentary considers the future of endowed chairs in academic medicine in the light of articles by Thorndyke and colleagues and by Chin-Hong and colleagues in this issue. The authors evaluate the traditional allocation of endowed chairs, which can attract and retain talented faculty and can support focused research far into the future, while other gifts may support more timely concerns, but over a shorter term. The authors weigh the benefits and challenges of allocation of endowed chairs, such as the need to improve representation, diversity, equity, and inclusion, and opportunities to support early-career investigators or research teams. New endowed positions can be challenging to establish, as there may be competition with learner scholarship programs and programmatic support. Leadership turnover of university presidents and deans can slow philanthropic growth and make recruitment and fundraising for new positions even more challenging. The authors discuss the balance of institutional priorities and ways to use endowed chairs for scholarship in evolving areas of medicine and science. They further suggest working with donors to develop more adaptable gift agreements, which will allow institutions to transform endowed positions to meet changing needs while preserving the intentions of the donor. To maintain endowed chairs as a worthwhile and relevant outlet for philanthropy, one which donors will enthusiastically support, it is essential to align them with the changing needs of the institution and the broader environment of academic medicine.

Rare coding variants in ten genes confer substantial risk for schizophrenia.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

International Medical Graduates in the United States Psychiatry Workforce.

OBJECTIVE: This study describes the supply, distribution, and characteristics of international medical graduate (IMG) psychiatrists who provide services in the USA. METHODS: Cross-sectional study design, using descriptive statistics based on combined data from the American Medical Association (2020 Physician Masterfile) and the Educational Commission for Foreign Medical Graduates. RESULTS: International medical graduates continue to make significant contributions to the US physician workforce. As a group, they represent 29% of active psychiatrists in the USA, compared to 23% in all other medical specialties. Many IMG psychiatrists were US citizens who obtained their medical degrees outside the USA or Canada, often in the Caribbean. In some states (i.e., Florida, New Jersey), over 40% of active psychiatrists are IMGs. Over 30% of IMG psychiatrists graduated from medical schools in India and Pakistan. CONCLUSIONS: This study provides an overview of the psychiatric workforce in the USA, quantifying the specific contribution of IMGs. Several factors, including immigration policies, continued expansion of US medical schools, and the number of available residency positions, could impact the flow of IMGs to the US. Longitudinal studies are needed to better understand the implications for workforce composition and distribution, and their potential impact on the care of psychiatric patients.

25-Hydroxyvitamin D and metabolic-related laboratory values in women with schizophrenia and hyperprolactinemia.

Schizophrenia is a severe mental disorder with various medical comorbidities and early mortality. Hyperprolactinemia is common in women and its impact on sexual function, galactorrhea and amenorrhea is well known. This paper evaluates the risk of 25-hydroxy vitamin D deficiency and other metabolic related laboratory abnormalities in women with schizophrenia having hyperprolactinemia (N = 43). The mean prolactin level in these women was 88.5 ± 56.0 ng/mL. We found that 100% of women were overweight of which 74% (32/43) of the women were obese, 56% (23/41) had abnormal total cholesterol levels and 30% (13/43) had high fasting blood glucose. Vitamin D levels were considered deficient or inadequate in 37% of women. We did not see significant correlations of prolactin with laboratory measures, however all female patients had elevated and high prolactin levels, leading to low variability in a small sample, which may have precluded seeing any direct relationships. Recognizing prolactin related side effects and understanding the role of other health measures seen in women with antipsychotic induced hyperprolactinemia in our female patients are critical steps toward better personalization of their care and recovery.

Prognostic value of polygenic risk scores for adults with psychosis.

Polygenic risk scores (PRS) summarize genetic liability to a disease at the individual level, and the aim is to use them as biomarkers of disease and poor outcomes in real-world clinical practice. To date, few studies have assessed the prognostic value of PRS relative to standards of care. Schizophrenia (SCZ), the archetypal psychotic illness, is an ideal test case for this because the predictive power of the SCZ PRS exceeds that of most other common diseases. Here, we analyzed clinical and genetic data from two multi-ethnic cohorts totaling 8,541 adults with SCZ and related psychotic disorders, to assess whether the SCZ PRS improves the prediction of poor outcomes relative to clinical features captured in a standard psychiatric interview. For all outcomes investigated, the SCZ PRS did not improve the performance of predictive models, an observation that was generally robust to divergent case ascertainment strategies and the ancestral background of the study participants.

A Meta-Analysis of Brain-Derived Neurotrophic Factor Effects on Brain Volume in Schizophrenia: Genotype and Serum Levels.

AIM: The Val66Met single-nucleotide polymorphism (SNP) on the BDNF gene has established pleiotropic effects on schizophrenia incidence and morphologic alterations in the illness. The effects of brain-derived neurotrophic factor (BDNF) on brain volume measurements are however mixed seeming to be less established for most brain regions. The current meta-analytic review examined (1) the association of the Val66Met SNP and brain volume alterations in schizophrenia by comparing Met allele carriers to Val/Val homozygotes and (2) the association of serum BDNF with brain volume measurements. METHOD: Studies included in the meta-analyses were identified through an electronic search of PubMed and PsycInfo (via EBSCO) for English language publications from January 2000 through December 2017. Included studies had conducted a genotyping procedure of Val66Met or obtained assays of serum BDNF and obtained brain volume data in patients with psychotic disorders. Nonhuman studies were excluded. RESULTS: Study 1 which included 52 comparisons of Met carriers and Val/Val homozygotes found evidence of lower right and left hippocampal volumes among Met allele carriers with schizophrenia. Frontal measurements, while also lower among Met carriers, did not achieve statistical significance. Study 2 which included 7 examinations of the correlation between serum BDNF and brain volume found significant associations between serum BDNF levels and right and left hippocampal volume with lower BDNF corresponding to lower volumes. DISCUSSION: The meta-analyses provided evidence of associations between brain volume alterations in schizophrenia and variations on the Val66Met SNP and serum BDNF. Given the limited number of studies, it remains unclear if BDNF effects are global or regionally specific.

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. METHODS: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. RESULTS: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572. CONCLUSIONS: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

Treatment-Resistant Schizophrenia.

Although, gratifyingly, research on the treatment of schizophrenia has increasingly focused on first-episode and prodromal patient populations, it is still recognized that many patients with more chronic illnesses exhibit a suboptimal response to treatments. This suboptimal response with continuation of symptoms is represented in the term treatment-resistant schizophrenia (TRS). This article addresses contemporary definitions as well as updated guidelines for patients with TRS.

Distinguishing patterns of impairment on inhibitory control and general cognitive ability among bipolar with and without psychosis, schizophrenia, and schizoaffective disorder.

BACKGROUND: Deficits in inhibitory control on a Stop Signal Task (SST) were previously observed to be of similar magnitude across schizophrenia, schizoaffective, and bipolar disorder with psychosis, despite variation in general cognitive ability. Understanding different patterns of performance on the SST may elucidate different pathways to the impaired inhibitory control each group displayed. Comparing nonpsychotic bipolar disorder to the psychosis groups on SST may also expand our understanding of the shared neurobiology of this illness spectrum. METHODS: We tested schizophrenia (n = 220), schizoaffective (n = 216), bipolar disorder with (n = 192) and without psychosis (n = 67), and 280 healthy comparison participants with a SST and the Brief Assessment of Cognition in Schizophrenia (BACS), a measure of general cognitive ability. RESULTS: All patient groups had a similar degree of impaired inhibitory control over prepotent responses. However, bipolar groups differed from schizophrenia and schizoaffective groups in showing speeded responses and inhibition errors that were not accounted for by general cognitive ability. Schizophrenia and schizoaffective groups had a broader set of deficits on inhibition and greater general cognitive deficit, which fully accounted for the inhibition deficits. No differences were found between the clinically well-matched bipolar with and without psychosis groups, including for inhibitory control or general cognitive ability. CONCLUSIONS: We conclude that 1) while impaired inhibitory control on a SST is of similar magnitude across the schizo-bipolar spectrum, including nonpsychotic bipolar, different mechanisms may underlie the impairments, and 2) history of psychosis in bipolar disorder does not differentially impact inhibitory behavioral control or general cognitive abilities.

Leadership Development for Future Medical School Deans: Outcomes of the AAMC Council of Deans Fellowship Program.

PURPOSE: To determine the outcomes of the Association of American Medical Colleges (AAMC) Council of Deans (COD) Fellowship Program with respect to participants' achieving the goals of becoming a medical school dean and developing leadership skills, and to ascertain fellows' views about the program's value, beneficial aspects, and areas for improvement. METHOD: The 37 COD fellows from 2002 to 2016 were invited to participate in a 2017 survey addressing demographics, training, current leadership position, and value of the program. The survey also included 3 open-ended questions. A 2018 web-based search was conducted to determine fellows' senior leadership roles since their program participation. RESULTS: The survey response rate was 73% (27/37). The majority of respondents were male (82%, 22), aged 51-70 (89%, 25), and white (82%, 22). The top 5 medical specialties reported were internal medicine, pediatrics, anesthesiology, psychiatry, and surgery. Most respondents (63%, 17) reported having a graduate degree. All reported being in leadership positions in academia and/or health care. The web-based search found that 27% (10/37) of the fellows became medical school deans (average tenure 5.6 years); 2 fellows became deans of other types of schools. Overall, survey respondents perceived the program as valuable. Respondents identified shadowing a dean mentor, attending COD meetings, and attending the AAMC Executive Development Seminar for Deans as the most valuable program components. The majority (88%, 23/26) indicated their fellow experience persuaded them to pursue being a dean; 2 (8%) indicated it did not. Respondents identified 4 key opportunities for program improvement: more sponsorship by deans, development of a learning community, enhanced mentoring, and coaching. CONCLUSIONS: The COD Fellowship Program appears to be successful in preparing senior faculty to become deans and assume other senior leadership roles in academia and/or health care. Fellows' feedback will be used to inform future revisions to the program.

Inflammation, Antipsychotic Drugs, and Evidence for Effectiveness of Anti-inflammatory Agents in Schizophrenia.

In recent years, there is a new optimism in schizophrenia therapeutics with the emergence of immunomodulation as a potential treatment approach. Current evidence points to various immunological abnormalities in schizophrenia, including cell-mediated processes, acute phase proteins, cytokines, and intracellular mediators. Trait- and state-related immune dysfunction appears to exist, and a strong case can therefore be made for immunomodulation therapies in the prevention, treatment, and/or moderating the course of schizophrenia.Immunomodulation approaches include use of nonsteroidal anti-inflammatory agents to stop or moderate an over-activated inflammatory process, anti-oxidants, nutrients, vitamins, herbal products, and other neuroprotection agents that inhibit pro-inflammatory processes, optimal use of antipsychotic drugs (APDs) that may have anti-inflammatory actions or in certain cases such as clozapine may enhance blunted inflammatory responses, and biological agents to antagonize specific immune mediators such as the cytokines. A combination of two or more of the above approaches is also worthy of consideration.In this chapter, the available data for each of the above approaches is reviewed and discussed. Strengths and limitations of current studies are identified, and suggestions are made for future studies. For example, identifying patients with high levels of specific biomarkers such as C-Reactive Protein, IL-6, IFN-γ, TNF-α, and genetic polymorphisms of cytokines, and match them with clinical subgroups such as prodromal, first episode psychosis, chronic psychosis, and negative symptoms with the aim of developing targeted treatment approaches and more personalized medicine. Meanwhile, since the science and trial data are not advanced enough to make definitive recommendations, clinicians should stay up to date with the literature, obtain detailed immunological histories, and review the risk-benefit ratio of adding available immune modulating agents to standard therapies, to provide optimal and state-of-the-art care to patients.

Neuroinflammation and Schizophrenia.

PURPOSE OF REVIEW: There are longstanding, intriguing findings of immune dysfunction in schizophrenia. These findings span peripheral immune markers, especially cytokine abnormalities. RECENT FINDINGS: This review describes recent genetic and immune marker studies and emergent treatment studies. Collectively, this provides a synthesis and current appraisal of the neuroimmune hypothesis of schizophrenia.

Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases.

BACKGROUND: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. CONCLUSIONS: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

Insomnia and suicidal ideation in nonaffective psychosis.

Study Objectives: Insomnia is a common symptom in the clinical course of schizophrenia. There is a robust association between insomnia and suicidality in other psychiatric disorders. Two previous studies found associations between insomnia and suicide attempt or completed suicide in patients with schizophrenia. We hypothesized that greater insomnia would be associated with greater levels of suicidal ideation in patients with schizophrenia and other nonaffective psychoses. Methods: We recruited 108 inpatients and outpatients age 18-65 between July 2010 and July 2016 with DSM-IV nonaffective psychosis (schizophrenia, schizoaffective disorder, or schizophreniform disorder). We investigated relationships between current insomnia (Insomnia Severity Index [ISI]), suicidal ideation over the past week, and lifetime history of suicide attempt (Beck Scale for Suicide Ideation [BSS]) in regression analyses. Results: After controlling for potential confounders, insomnia was a significant indicator of suicidal ideation (ß = 0.27, p = 0.032). Insomnia was also a significant indicator of a high BSS score (≥16; OR = 1.14, 95% CI: 1.01-1.28, p = 0.029). Furthermore, participants with severe insomnia were almost 15 times more likely to have a lifetime history suicide attempt than participants without current insomnia (OR = 14.8, 95% CI: 1.4-157, p = 0.025). Insomnia was also an indicator of greater PANSS total (ß = 0.33, p = 0.001), positive subscale (ß = 0.32, p = 0.002), and general subscale (ß = 0.40, p < 0.001) scores. Conclusions: Insomnia is associated with suicidal ideation, lifetime suicide attempt, and greater psychopathology in patients with schizophrenia. Our findings suggest that formal assessment of insomnia may be germane to the clinical care of patients with schizophrenia as a marker of suicide risk and symptom severity.