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.

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.

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.

Adjunct Aripiprazole Reduces Prolactin and Prolactin-Related Adverse Effects in Premenopausal Women With Psychosis: Results From the DAAMSEL Clinical Trial.

PURPOSE/BACKGROUND: Prolactin-related adverse effects contribute to nonadherence and adverse health consequences, particularly in women with severe mental illness. Treating these adverse effects may improve treatment acceptability, adherence, and long-term outcomes. METHODS/PROCEDURES: Premenopausal women with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder were recruited for a randomized, double-blind, placebo-controlled 16-week trial of adjunct aripiprazole (5-15 mg/d). Participants had elevated prolactin (>24 ng/mL) and were experiencing galactorrhea, amenorrhea, oligomenorrhea, or sexual dysfunction on a prolactin-elevating antipsychotic. Participants were evaluated biweekly for prolactin elevation and galactorrhea and completed a menstrual diary review. Psychiatric symptoms and adverse effects were closely monitored. FINDINGS/RESULTS: Forty-six women were randomized (n = 25 aripiprazole, n = 21 placebo). Thirty-seven completed at least 8 weeks of the study (n = 20 [80%] aripiprazole and n = 17 [81%] placebo). Aripiprazole (mean dose, 11.7 ± 2.4 mg/d) was effective for lowering prolactin relative to placebo (P = 0.04). In addition, 45% (9/20) of the aripiprazole group had a normalized prolactin (<24 mg/mL) compared with 12% (2/17) of the placebo group (P = 0.028). Galactorrhea resolved in 77% (10/13) of the aripiprazole-treated participants compared with 33% (4/12) in the placebo group (P = 0.028). Normalization of sexual function (<16 on the Arizona Sexual Experience Scale) occurred in 50% on aripiprazole (7/14) versus 9% (1/11) on placebo (P = 0.030). No differences between groups in symptoms or adverse effects were noted. Overall, women rated a mean score of 4.6 ± 0.6 on a 5-point Likert scale for sexual function improvement, suggesting their particular satisfaction with improvement in this domain. IMPLICATIONS/CONCLUSIONS: Building upon prior studies, this rigorous evaluation confirms the utility of adjunctive aripiprazole as a strategy for improving prolactin and managing prolactin-related adverse effects in premenopausal women with psychosis.

Electronic cigarette use in patients with schizophrenia: Prevalence and attitudes.

BACKGROUND: Smoking is highly prevalent in patients with schizophrenia. Electronic cigarettes (e-cigarettes) are becoming increasingly popular among smokers. Surveys indicate overall favorable attitudes toward the use of e-cigarettes to reduce or quit smoking, relieve withdrawal symptoms, and with respect to perceived health risks; however, less is known about their use in patients with schizophrenia. In the present study, we investigated the prevalence of and attitudes toward e-cigarettes in patients with schizophrenia. METHODS: Sixty inpatients and outpatients age 18 to 70 with schizophrenia completed a brief survey on e-cigarette use. RESULTS: Thirty-seven percent of participants reported having tried e-cigarettes, 24% of never-users were considering use, and 7% were current users. Thirty-four percent of surveyed patients believed that the health effects of e-cigarettes were less harmful than regular cigarettes. Health benefits (39%), cutting down (37%), and quitting smoking (37%) were the most frequently cited potential advantages, whereas cost (33%) was the most common potential disadvantage of e-cigarettes. Participants who were ever-users reported that regular cigarettes were significantly more helpful with reducing symptoms such as depression/anxiety, impaired concentration, and paranoia, than e-cigarettes (P < .05 for each). CONCLUSIONS: These preliminary findings should be investigated in larger samples, but suggest that e-cigarettes have, at best, modest relevance to smoking cessation in patients with schizophrenia.

Prioritizing Harm.

In this study, we examined if a self-report of trait spite, the Spitefulness Scale, retains the same associations with dark personality traits in individuals with severe mental illness. We also examine if reports on the Spitefulness Scale are correlated with observed spiteful behavior in a game developed to offer opportunities for spite. One hundred twenty individuals clinically diagnosed with psychotic spectrum disorders and receiving inpatient treatment at a state hospital participated in this study and completed measures of personality. The Spitefulness Scale retained its associations with measures of dark personality traits in individuals with psychosis. Spitefulness Scale scores were also related to a performance measure of spite and spite was evidenced by a significant proportion of participants across measures (20.8%-26.7%). These data suggest the presence of spite as it is understood in the general population in a significant subset of individuals with psychosis. Spite could be considered an independent personality trait and part of the family of dark personality traits.

Paternal age effect: Replication in schizophrenia with intriguing dissociation between bipolar with and without psychosis.

Advanced paternal age (APA) is a risk factor for schizophrenia (Sz) and bipolar disorder (BP). Putative mechanisms include heritable genetic factors, de novo mutations, and epigenetic mechanisms. Few studies have explored phenotypic features associated with APA. The Genomic Psychiatry Cohort established a clinically characterized repository of genomic samples from subjects with a Sz-BP diagnosis or unaffected controls, 12,975 with parental age information. We estimated relative risk ratios for Sz, schizoaffective depressed and bipolar types (SA-D, SA-B), and BP with and without history of psychotic features (PF) relative to the control group, comparing each paternal age group to the reference group 20-24 years. All tests were two-sided with adjustment for multiple comparisons. Subjects with fathers age 45+ had significantly higher risk for all diagnoses except for BP w/o PF. APA also bore no significant relation to family psychiatric history. In conclusion, we replicated APA as a risk factor for Sz. To our knowledge, this is the first published report of APA in a BP sample stratified by psychosis history, extending this association only in BP w/PF. This suggests that phenotypic expression of the APA effect in Sz-BP spectrum is psychosis, per se, rather than other aspects of these complex disorders. The lack of a significant relationship between paternal age and familial disease patterns suggests that underlying mechanisms of the paternal age effect may involve a complex interaction of heritable and non-heritable factors. The authors discuss implications and testable hypotheses, starting with a focus on genetic mechanisms and endophenotypic expressions of dopaminergic function. © 2015 Wiley Periodicals, Inc.

The professional experiences of peer specialists in the Georgia Mental Health Consumer Network.

There has been an increase in the number of peer-led services within the mental health care system. There however remains little information about the experiences of peers serving in such helping roles. This study explored the professional experiences of peer specialists including the basic roles, benefits, and potential challenges of the peer specialist role. Peer specialists (N = 84) completed a battery of surveys and questionnaires. Qualitative analysis of participants' responses indicated that peer specialists face difficulties such as poor compensation, limited employment opportunities, work stress, emotional stress in helping others, and maintaining personal wellness. Quantitative analyses revealed that recovery attitudes may confer clinical and psychosocial benefits for peer specialists and employment may contribute to hope, empowerment, social engagement, and competence. Peer specialists would benefit from resources and supports aimed at their continued training and supervision. Fostering the vocational advancement of peer specialists could potentially enhance their experiential recovery and community functioning.

The Use of Simulation to Teach Suicide Risk Assessment to Health Profession Trainees-Rationale, Methodology, and a Proof of Concept Demonstration with a Virtual Patient.

OBJECTIVE: There is increasing use of educational technologies in medical and surgical specialties. Described herein is the development and application of an interactive virtual patient (VP) to teach suicide risk assessment to health profession trainees. We studied the effect of the following: (1) an interaction with a bipolar VP who attempts suicide or (2) completion of a video-teaching module on interviewing a bipolar patient, on medical students' proficiency in assessing suicide risk in standardized patients. We hypothesized that students who interact with a bipolar VP will be at least as likely to assess suicide risk, as their peers who completed a video module. METHODS: In a randomized, controlled study, we compared the frequency with which second-year students at the Medical College of Georgia asked suicide risk and bipolar symptoms questions by VP/video group. RESULTS: We recruited 67 students. The VP group inquired more frequently than the video group in 4 of 5 suicide risk areas and 11 of 14 other bipolar symptomatology areas. There were minimal to small effect sizes in favor of the VP technology. The students preferred the video over the VP as an educational tool (p = 0.007). CONCLUSIONS: Our study provides proof of concept that both VP and video module approaches are feasible for teaching students to assess suicide risk, and we present evidence about the role of active learning to improve communication skills. Depending on the learning context, interviewing a VP or observation of a videotaped interview can enhance the students' suicide risk assessment proficiency in an interview with a standardized patient. An interactive VP is a plausible modality to deliver basic concepts of suicide risk assessment to medical students, can facilitate individual preferences by providing easy access and portability, and has potential generalizability to other aspects of psychiatric training.

Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial.

IMPORTANCE: Long-acting injectable antipsychotics are used to reduce medication nonadherence and relapse in schizophrenia-spectrum disorders. The relative effectiveness of long-acting injectable versions of second-generation and older antipsychotics has not been assessed. OBJECTIVE: To compare the effectiveness of the second-generation long-acting injectable antipsychotic paliperidone palmitate with the older long-acting injectable antipsychotic haloperidol decanoate. DESIGN, SETTING, AND PARTICIPANTS: Multisite, double-blind, randomized clinical trial conducted from March 2011 to July 2013 at 22 US clinical research sites. Randomized patients (n = 311) were adults diagnosed with schizophrenia or schizoaffective disorder who were clinically assessed to be at risk of relapse and likely to benefit from a long-acting injectable antipsychotic. INTERVENTIONS: Intramuscular injections of haloperidol decanoate 25 to 200 mg or paliperidone palmitate 39 to 234 mg every month for as long as 24 months. MAIN OUTCOME MEASURES: Efficacy failure, defined as a psychiatric hospitalization, a need for crisis stabilization, a substantial increase in frequency of outpatient visits, a clinician's decision that oral antipsychotic could not be discontinued within 8 weeks after starting the long-acting injectable antipsychotics, or a clinician's decision to discontinue the assigned long-acting injectable due to inadequate therapeutic benefit. Key secondary outcomes were common adverse effects of antipsychotic medications. RESULTS: There was no statistically significant difference in the rate of efficacy failure for paliperidone palmitate compared with haloperidol decanoate (adjusted hazard ratio, 0.98; 95% CI, 0.65-1.47). The number of participants who experienced efficacy failure was 49 (33.8%) in the paliperidone palmitate group and 47 (32.4%) in the haloperidol decanoate group. On average, participants in the paliperidone palmitate group gained weight and those in the haloperidol decanoate group lost weight; after 6 months, the least-squares mean weight change for those taking paliperidone palmitate was increased by 2.17 kg (95% CI, 1.25-3.09) and was decreased for those taking haloperidol decanoate (-0.96 kg; 95% CI, -1.88 to -0.04). Patients taking paliperidone palmitate had significantly higher maximum mean levels of serum prolactin (men, 34.56 µg/L [95% CI, 29.75-39.37] vs 15.41 µg/L [95% CI, 10.73-20.08]; P <.001, and for women, 75.19 [95% CI, 63.03-87.36] vs 26.84 [95% CI, 13.29-40.40]; P<.001). Patients taking haloperidol decanoate had significantly larger increases in global ratings of akathisia (0.73 [95% CI, 0.59-0.87] vs 0.45 [95% CI, 0.31-0.59]; P=.006). CONCLUSIONS AND RELEVANCE: In adults with schizophrenia or schizoaffective disorder, use of paliperidone palmitate vs haloperidol decanoate did not result in a statistically significant difference in efficacy failure, but was associated with more weight gain and greater increases in serum prolactin, whereas haloperidol decanoate was associated with more akathisia. However, the CIs do not rule out the possibility of a clinically meaningful advantage with paliperidone palmitate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01136772.

The medical school dean: leadership and workforce development.

OBJECTIVE: The author reviews the role of deans in US academic medical centers. METHODS: The author describes the role of the dean of a medical school on the basis of his personal experience and key texts on the topic. RESULTS: Skills acquired earlier in an academic career are used across a much broader base in the role of dean, and the dean holds a time-honored and privileged position in academic medicine. Fundamental activities of the dean include communication, mentorship, recruitment, and retention. CONCLUSION: As with any leadership role, the position is not about the person, and a dean serves as a resource to a host of internal constituents and as an ambassador for the institution.

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.

Neuroimaging schizophrenia: a picture is worth a thousand words, but is it saying anything important?

Schizophrenia is characterized by neurostructural and neurofunctional aberrations that have now been demonstrated through neuroimaging research. The article reviews recent studies that have attempted to use neuroimaging to understand the relation between neurological abnormalities and aspects of the phenomenology of schizophrenia. Neuroimaging studies show that neurostructural and neurofunctional abnormalities are present in people with schizophrenia and their close relatives and may represent putative endophenotypes. Neuroimaging phenotypes predict the emergence of psychosis in individuals classified as high-risk. Neuroimaging studies have linked structural and functional abnormalities to symptoms; and progressive structural changes to clinical course and functional outcome. Neuroimaging has successfully indexed the neurotoxic and neuroprotective effects of schizophrenia treatments. Pictures can inform about aspects of the phenomenology of schizophrenia including etiology, onset, symptoms, clinical course, and treatment effects but this assertion is tempered by the scientific and practical limitations of neuroimaging.

The genomic psychiatry cohort: partners in discovery.

The Genomic Psychiatry Cohort (GPC) is a longitudinal resource designed to provide the necessary population-based sample for large-scale genomic studies, studies focusing on Research Domain Criteria (RDoC) and/or other alternate phenotype constructs, clinical and interventional studies, nested case-control studies, long-term disease course studies, and genomic variant-to-phenotype studies. We provide and will continue to encourage access to the GPC as an international resource. DNA and other biological samples and diagnostic data are available through the National Institute of Mental Health (NIMH) Repository. After appropriate review and approval by an advisory board, investigators are able to collaborate in, propose, and co-lead studies involving cohort participants.

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.

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.

Turnover of first-time Chairs in departments of psychiatry.

OBJECTIVE: The authors examine the tenure of first-time Chairs in academic departments of psychiatry in order to stimulate discussion on extant workforce and leadership issues. METHOD: Data on tenure of Chairs in psychiatry and other nonsurgical specialties were derived from the longitudinal database of the Association of American Medical Colleges and evaluated for successive 4-year epochs between 1983 and 2002. RESULTS: The 5-year retention rate of Chairs of academic departments of psychiatry is 68%, and the 10-year retention rate drops sharply to 39%, similar to other specialties. CONCLUSION: Although most first-time Chairs of psychiatry last 5 years in their position, much fewer remain 10 years or longer. Therefore, efforts to promote succession planning for academic leadership in psychiatry are warranted.