Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.

The Disrupted in Schizophrenia 1 (DISC1) gene is disrupted by a balanced chromosomal translocation (1; 11) (q42; q14.3) in a Scottish family with a high incidence of major depression, schizophrenia, and bipolar disorder. Subsequent studies provided indications that DISC1 plays a role in brain development. Here, we demonstrate that suppression of DISC1 expression reduces neural progenitor proliferation, leading to premature cell cycle exit and differentiation. Several lines of evidence suggest that DISC1 mediates this function by regulating GSK3beta. First, DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. Importantly, expression of stabilized beta-catenin overrides the impairment of progenitor proliferation caused by DISC1 loss of function. Furthermore, GSK3 inhibitors normalize progenitor proliferation and behavioral defects caused by DISC1 loss of function. Together, these results implicate DISC1 in GSK3beta/beta-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.

National Network of Depression Centers' Recommendations on Harmonizing Clinical Documentation of Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.

Psychiatric polygenic risk scores: Child and adolescent psychiatrists' knowledge, attitudes, and experiences.

Psychiatric polygenic risk scores (PRS) have potential utility in psychiatric care and prevention, but there are concerns about their implementation. We surveyed 960 US-based practicing child and adolescent psychiatrists' (CAP) about their experiences, perspectives, and potential uses of psychiatric PRS. While 23% of CAP reported that they had never heard of PRS, 10 % of respondents have had a patient/family bring PRS to them and 4% have generated PRS for patients. Though 25% stated they would request PRS if a patient/caregiver asked, 35% indicated that nothing would prompt them to request PRS. Most respondents (54%) believed psychiatric PRS are currently at least slightly useful and 87% believed they will be so in 5 years. More than 70% indicated they would take action in response to a child with a top fifth percentile psychiatric PRS but no diagnosis: 48% would increase monitoring of symptoms, 42% would evaluate for current symptoms, and 4% would prescribe medications. Yet, most respondents were concerned that high-PRS results could lead to overtreatment and negatively impact patients' emotional well-being. Findings indicate emerging use of psychiatric PRS within child and adolescent psychiatry in the US. It is critical to examine the ethical and clinical challenges that PRS may generate and begin efforts to promote their informed and responsible use.

Sex differences associated with corpus callosum development in human infants: A longitudinal multimodal imaging study.

The corpus callosum (CC) is the largest connective pathway in the human brain, linking cerebral hemispheres. There is longstanding debate in the scientific literature whether sex differences are evident in this structure, with many studies indicating the structure is larger in females. However, there are few data pertaining to this issue in infancy, during which time the most rapid developmental changes to the CC occur. In this study, we examined longitudinal brain imaging data collected from 104 infants at ages 6, 12, and 24 months. We identified sex differences in brain-size adjusted CC area and thickness characterized by a steeper rate of growth in males versus females from ages 6-24 months. In contrast to studies of older children and adults, CC size was larger for male compared to female infants. Based on diffusion tensor imaging data, we found that CC thickness is significantly associated with underlying microstructural organization. However, we observed no sex differences in the association between microstructure and thickness, suggesting that the role of factors such as axon density and/or myelination in determining CC size is generally equivalent between sexes. Finally, we found that CC length was negatively associated with nonverbal ability among females.

International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic).

Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.

International Society of Psychiatric Genetics Ethics Committee: Issues facing us.

Psychiatric genetics research is improving our understanding of the biological underpinnings of neurodiversity and mental illness. Using psychiatric genetics in ways that maximize benefits and minimize harms to individuals and society depends largely on how the ethical, legal, and social implications (ELSI) of psychiatric genetics are managed. The International Society of Psychiatric Genetics (ISPG) is the largest international organization dedicated to psychiatric genetics. Given its history, membership, and international reach, we believe the ISPG is well-equipped to contribute to the resolution of these ELSI challenges. As such, we recently created the ISPG Ethics Committee, an interdisciplinary group comprised of psychiatric genetics researchers, clinical geneticists, genetic counselors, mental health professionals, patients, patient advocates, bioethicists, and lawyers. This article highlights key ELSI challenges identified by the ISPG Ethics Committee to be of paramount importance for the ethical translation of psychiatric research into society in three contexts: research settings, clinical settings, and legal proceedings. For each of these arenas, we identify and discuss pressing psychiatric genetics ELSI dilemmas that merit attention and require action. The goal is to increase awareness about psychiatric genetics ELSI issues and encourage dialogue and action among stakeholders.

Altered corpus callosum morphology associated with autism over the first 2 years of life.

Numerous brain imaging studies indicate that the corpus callosum is smaller in older children and adults with autism spectrum disorder. However, there are no published studies examining the morphological development of this connective pathway in infants at-risk for the disorder. Magnetic resonance imaging data were collected from 270 infants at high familial risk for autism spectrum disorder and 108 low-risk controls at 6, 12 and 24 months of age, with 83% of infants contributing two or more data points. Fifty-seven children met criteria for ASD based on clinical-best estimate diagnosis at age 2 years. Corpora callosa were measured for area, length and thickness by automated segmentation. We found significantly increased corpus callosum area and thickness in children with autism spectrum disorder starting at 6 months of age. These differences were particularly robust in the anterior corpus callosum at the 6 and 12 month time points. Regression analysis indicated that radial diffusivity in this region, measured by diffusion tensor imaging, inversely predicted thickness. Measures of area and thickness in the first year of life were correlated with repetitive behaviours at age 2 years. In contrast to work from older children and adults, our findings suggest that the corpus callosum may be larger in infants who go on to develop autism spectrum disorder. This result was apparent with or without adjustment for total brain volume. Although we did not see a significant interaction between group and age, cross-sectional data indicated that area and thickness differences diminish by age 2 years. Regression data incorporating diffusion tensor imaging suggest that microstructural properties of callosal white matter, which includes myelination and axon composition, may explain group differences in morphology.

Ethical Dilemmas and Countertransference in Legally Mandated Reporting of Fatal Child Neglect.

In the fall of 2019, a much-publicized court case brought to national attention the issues of patient-doctor confidentiality when it comes to reporting the deaths of newborns in the United States. It is unclear whether the recent overturning of Roe v. Wade will lead to more cases like this. This article discusses issues of countertransference, as well as the ethical and legal implications were it to be a psychiatrist, in active treatment of such a patient, who would be required to make such a report. More specifically, as in the publicized court case, the patient could be a minor at the time, receiving treatment from a child psychiatrist. The implications of such a case include how countertransference affects the perception of fatal child neglect compared to intentional neonaticide; the ethical dilemma of generating a mandated report with the goal of child safety when such a report could lead to real legal consequences for a minor child; and considerations regarding continued treatment of a patient after such a report is made. It is likely that countertransference, shaped by attitudes toward mothers and idealized views on mothering, may play a large role in all these circumstances.

Psychiatric polygenic risk scores: Experience, hope for utility, and concerns among child and adolescent psychiatrists.

Recent advances in psychiatric genetics have enabled the use of polygenic risk scores (PRS) to estimate genetic risk for psychiatric disorders. However, the potential use of PRS in child and adolescent psychiatry has raised concerns. This study provides an in-depth examination of attitudes among child and adolescent psychiatrists (CAP) regarding the use of PRS in psychiatry. We conducted semi-structured interviews with U.S.-based CAP (n = 29) who possess expertise in genetics. The majority of CAP indicated that PRS have limited clinical utility in their current form and are not ready for clinical implementation. Most clinicians stated that nothing would motivate them to generate PRS at present; however, some exceptions were noted (e.g., parent/family request). Clinicians spoke to challenges related to ordering, interpreting, and explaining PRS to patients and families. CAP raised concerns regarding the potential for this information to be misinterpreted or misused by patients, families, clinicians, and outside entities such as insurance companies. Finally, some CAP noted that PRS may lead to increased stigmatization of psychiatric disorders, and at the extreme, could be used to support eugenics. As PRS testing increases, it will be critical to examine CAP and other stakeholders' views to ensure responsible implementation of this technology.

Child and Adolescent Psychiatrists' Use, Attitudes, and Understanding of Genetic Tests in Clinical Practice.

Objective: To report current practices and attitudes of child and adolescent psychiatrists (CAP) regarding diagnostic genetic and pharmacogenetic (PGx) testing. Methods: Survey of 958 US-based practicing CAP. Results: 54.9% of respondents indicated that they had ordered/referred for a genetic test in the past 12 months. 87% of respondents agreed that it is their role to discuss genetic information regarding psychiatric conditions with their patients; however, 45% rated their knowledge of genetic testing practice guidelines as poor/very poor. The most ordered test was PGx (32.2%), followed by chromosomal microarray (23.0%). 73.4% reported that PGx is at least slightly useful in child and adolescent psychiatry. Most (62.8%) were asked by a patient/family to order PGx in the past 12 months and 41.7% reported they would order PGx in response to a family request. Those who ordered a PGx test were more likely to have been asked by a patient/family and to work in private practice. 13.8% of respondents agreed/strongly agreed that a PGx test can predict the effectiveness of specific antidepressants. Some respondents also indicated they would make clinical changes based on PGx information even if a medication was currently effective and there were no side effects. Conclusions: Genetic testing has become routine clinical care in child and adolescent psychiatry. Despite this, many providers rate their associated knowledge as poor/very poor. Patient requests were associated with ordering practices and providers misinterpretation of PGx may be leading to unnecessary changes in clinical management. There is need for further education and support for clinicians.

Child and adolescent psychiatrists' use, attitudes, and understanding of genetic testing and pharmacogenetics in clinical practice.

The purpose of this study was to report current practices and attitudes of child and adolescent psychiatrists (CAP) regarding diagnostic genetic and pharmacogenetic (PGx) testing. We surveyed 958 US-based practicing CAP. 54.9% of respondents indicated that they had ordered/referred for a genetic test in the past 12 months. 87% of respondents agreed that it is their role to discuss genetic information regarding psychiatric conditions with their patients; however, 45% rated their knowledge of genetic testing practice guidelines as poor/very poor. The most ordered test was PGx (32.2%), followed by chromosomal microarray (23.0%). 73.4% reported that PGx is at least slightly useful in child and adolescent psychiatry. Most (62.8%) were asked by a patient/family to order PGx in the past 12 months and 41.7% reported they would order PGx in response to a family request. Those who ordered a PGx test were more likely to have been asked by a patient/family and to work in private practice. 13.8% of respondents agreed/strongly agreed that a PGx test can predict the effectiveness of specific antidepressants. Some respondents also indicated they would make clinical changes based on PGx information even if a medication was currently effective and there were no side effects. Genetic testing has become routine clinical care in child and adolescent psychiatry. Despite this, many providers rate their associated knowledge as poor/very poor. Patient requests were associated with ordering practices and providers misinterpretation of PGx may be leading to unnecessary changes in clinical management. There is need for further education and support for clinicians.

Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of ß-secretase (BACE1).

Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid ß (Aß) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aß, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aß, as well as the APP processing enzyme, ß-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aß plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aß levels in the CK-p25 mouse to those of wild-type mice via the partial genetic deletion of BACE1, allowing us to examine the Aß-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aß levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aß-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aß production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD.

Incorporation of Telepsychiatry for Patients with Developmental Disorders into Routine Clinical Practice-A Survey of Specialty Clinics Adapting to Telepsychiatry During the COVID-19 Pandemic.

In 2020, a nationwide shift to telepsychiatry occurred in the wake of the Coronavirus Disease 2019 (COVID-19) pandemic and lockdowns. To assess the rates of telepsychiatry appointment attendance pre- and post-lockdown, we conducted a national, multi-site survey of appointments in 2020 compared to a similar time period in 2019, at outpatient child psychiatry clinics that specialize in the treatment of patients with Autism Spectrum Disorder (ASD) and/or Developmental Disabilities (DD). ASD/DD clinics rapidly shifted to telepsychiatry, returning to pre-pandemic appointment numbers and completion rates within months. We advocate for the continued funding of this care model, discuss the substantial benefits physicians, patients and families have found in using telepsychiatry, and suggest ways to improve future access for ASD/DD telepsychiatry.

Concerns about the use of polygenic embryo screening for psychiatric and cognitive traits.

Private companies have begun offering services to allow parents undergoing in-vitro fertilisation to screen embryos for genetic risk of complex diseases, including psychiatric disorders. This procedure, called polygenic embryo screening, raises several difficult scientific and ethical issues, as discussed in this Personal View. Polygenic embryo screening depends on the statistical properties of polygenic risk scores, which are complex and not well studied in the context of this proposed clinical application. The clinical, social, and ethical implications of polygenic embryo screening have barely been discussed among relevant stakeholders. To our knowledge, the International Society of Psychiatric Genetics is the first professional biomedical organisation to issue a statement regarding polygenic embryo screening. For the reasons discussed in this Personal View, the Society urges caution and calls for additional research and oversight on the use of polygenic embryo screening.

A dimensional perspective on the genetics of obsessive-compulsive disorder.

This review covers recent findings in the genomics of obsessive-compulsive disorder (OCD), obsessive-compulsive symptoms, and related traits from a dimensional perspective. We focus on discoveries stemming from technical and methodological advances of the past five years and present a synthesis of human genomics research on OCD. On balance, reviewed studies demonstrate that OCD is a dimensional trait with a highly polygenic architecture and genetic correlations to multiple, often comorbid psychiatric phenotypes. We discuss the phenotypic and genetic findings of these studies in the context of the dimensional framework, relying on a continuous phenotype definition, and contrast these observations with discoveries based on a categorical diagnostic framework, relying on a dichotomous case/control definition. Finally, we highlight gaps in knowledge and new directions for OCD genetics research.

Child and Adolescent Psychiatrists' Perceptions of Utility and Self-rated Knowledge of Genetic Testing Predict Usage for Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is associated with numerous genetic syndromes.1 Practice guidelines from various medical specialty societies, such as American Academy of Child and Adolescent Psychiatry (AACAP), American College of Medical Genetics, American Neurological Association, and American Academy of Pediatrics, indicate that genetic testing should be part of the evaluation for ASD.1-4 Studies have shown, however, that many patients do not receive indicated genetic testing; reported rates of testing vary widely, ranging from 1.5% to 60% of patients receiving genetic testing as part of the evaluation for ASD.4-8 Child and adolescent psychiatrists practicing in the United States (approximately 8300)9 far outnumber developmental behavioral pediatricians (approximately 900) and child neurologists (approximately 900), but in 1 study child and adolescent psychiatrists were the least likely to order genetic testing during the evaluation of patients with ASD diagnoses.6 Thus, it is critical to understand attitudes of child and adolescent psychiatrists toward genetic testing and other barriers to genetic testing to optimize adherence to practice guidelines for appropriate genetic testing in people with ASD. A survey to capture the current practice, knowledge, and perceptions toward genetic testing was developed by content matter experts that included child and adolescent psychiatrists, psychologists, and genetic counselors as well as lawyers, anthropologists, and bioethicists with expertise in ethical, legal, and social implications of genetics.

Ethical and Clinical Considerations During the Coronavirus Era.

The practice of child and adolescent psychiatry is evolving during an unprecedented global health catastrophe, the coronavirus disease 2019 (COVID-19) pandemic. As child and adolescent psychiatrists grapple with COVID-19's enormous medical, educational, social, and economic toll, a mental health crisis is co-occurring. Pre-existing disparities are recognized as contributors to the disproportionate impact of the COVID-19 pandemic on racial and ethnic minorities.1 The magnitude of COVID-19's effects on child and family mental health has yet to be fully revealed. child and adolescent psychiatrists are in a unique position to address this mental health crisis. Child and adolescent psychiatrists must stay up-to-date regarding federal, state, local, and institutional mandates, regulations, and policies informed by the Centers for Disease Control and Prevention2 and other public health institutions, while also navigating the ethical dilemmas unique to child and adolescent psychiatry during the coronavirus era.

Systematic Quality Improvement and Metabolic Monitoring for Individuals Taking Antipsychotic Drugs.

OBJECTIVE: The authors sought to increase the rate of cardiometabolic monitoring for patients receiving antipsychotic drugs in an academic outpatient psychiatric clinic serving people with serious mental illness. METHODS: Using a prospective quasi-experimental, interrupted time-series design with data from the electronic health record (EHR), the authors determined metabolic monitoring rates before, during, and after implementation of prespecified quality improvement (QI) measures between August 2016 and July 2017. QI measures included a combination of provider, patient, and staff education; systematic barrier reduction; and an EHR-based reminder system. RESULTS: After 1 year of QI implementation, the rate of metabolic monitoring had increased from 33% to 49% (p<0.01) for the primary outcome measure (hemoglobin A1C and lipid panel). This increased monitoring rate was sustained for 27 months beyond the end of the QI intervention. More than 75% of providers did not find the QI reminders burdensome. CONCLUSIONS: Significant improvement in the rate of metabolic monitoring for people taking antipsychotic drugs can be achieved with little added burden on providers. Future research needs to assess the full range of patient, provider, and system barriers that prevent cardiometabolic monitoring for all individuals receiving antipsychotic drugs.

LEGAL AND ETHICAL IMPLICATIONS OF CRISPR APPLICATIONS IN PSYCHIATRY.

Gene-environment interactions play a key role in how psychiatric disorders manifest and develop. Psychiatric genetics researchers are making progress in identifying genomic correlates of many disorders. And recently, the field of genetics has given rise to a technology that many claim will revolutionize the biological sciences and propel the field into a transformative phase: the powerful gene-editing tool known as CRISPR-Cas9. This Article illustrates which psychiatric conditions are likely to make an attractive target for CRISPR as the technology evolves and CRISPR therapies becomes a viable tool to manage or prevent disorders in a clinical setting. We examine the potential scientific and clinical challenges of applying CRISPR in the mental health context, along with the regulatory, ethical, and legal issues that might arise as a consequence of these applications.