Investigating assumptions of vulnerability: A case study of the exclusion of psychiatric inpatients as participants in genetic research in low‐ and middle‐income contexts

Psychiatric genetic research investigates the genetic basis of psychiatric disorders with the aim of more effectively understanding, treating, or, ultimately, preventing such disorders. Given the challenges of recruiting research participants into such studies, the potential for long‐term benefits of such research, and seemingly minimal risk, a strong claim could be made that all non‐acute psychiatric inpatients, including forensic and involuntary patients, should be included in such research, provided they have capacity to consent. There are tensions, however, regarding the ethics of recruiting psychiatric inpatients into such studies. In this paper our intention is to elucidate the source of these tensions from the perspective of research ethics committee interests and decision‐making. We begin by defining inpatient status and outline some of the assumptions surrounding the structures of inpatient care. We then introduce contemporary conceptions of vulnerability, including Florencia Luna’s account of vulnerability which we use as a framework for our analysis. While psychiatric inpatients could be subject to consent‐related vulnerabilities, we suggest that a particular kind of exploitation‐related vulnerability comes to the fore in the context of our case study. Moreover, a subset of these ethical concerns takes on particular weight in the context of genetic research in low‐ and middle‐income countries. At the same time, the automatic exclusion of inpatients from research elicits justice‐related vulnerabilities.     

Psychiatric research: psychoproteomics, degradomics and systems biology

While proteomics has excelled in several disciplines in biology (cancer, injury and aging), neuroscience and psychiatryproteomic studies are still in their infancy. Several proteomic studies have been conducted in different areas of psychiatric disorders, including drug abuse (morphine, alcohol and methamphetamine) and other psychiatric disorders (depression, schizophrenia and psychosis). However, the exact cellular and molecular mechanisms underlying these conditions have not been fully investigated. Thus, one of the primary objectives of this review is to discuss psychoproteomic application in the area of psychiatric disorders, with special focus on substance- and drug-abuse research. In addition, we illustrate the potential role of degradomic utility in the area of psychiatric research and its application in establishing and identifying biomarkers relevant to neurotoxicity as a consequence of drug abuse. Finally, we will discuss the emerging role of systems biology and its current use in the field of neuroscience and its integral role in establishing a comprehensive understanding of specific brain disorders and brain function in general.     

Psychiatric research: psychoproteomics,degradomics and systems biology

While proteomics has excelled in several disciplines in biology (cancer, injury and aging), neuroscience and psychiatryproteomic studies are still in their infancy. Several proteomic studies have been conducted in different areas of psychiatric disorders, including drug abuse (morphine, alcohol and methamphetamine) and other psychiatric disorders (depression, schizophrenia and psychosis). However, the exact cellular and molecular mechanisms underlying these conditions have not been fully investigated. Thus, one of the primary objectives of this review is to discuss psychoproteomic application in the area of psychiatric disorders, with special focus on substance- and drug-abuse research. In addition, we illustrate the potential role of degradomic utility in the area of psychiatric research and its application in establishing and identifying biomarkers relevant to neurotoxicity as a consequence of drug abuse. Finally, we will discuss the emerging role of systems biology and its current use in the field of neuroscience and its integral role in establishing a comprehensive understanding of specific brain disorders and brain function in general.     

New insights from the last decade of research in psychiatric genetics: discoveries,challenges and clinical implications

Psychiatric genetics has made substantial progress in the last decade, providing new insights into the genetic etiology of psychiatric disorders, and paving the way for precision psychiatry, in which individual genetic profiles may be used to personalize risk assessment and inform clinical decision-making. Long recognized to be heritable, recent evidence shows that psychiatric disorders are influenced by thousands of genetic variants acting together. Most of these variants are commonly occurring, meaning that every individual has a genetic risk to each psychiatric disorder, from low to high. A series of large-scale genetic studies have discovered an increasing number of common and rare genetic variants robustly associated with major psychiatric disorders. The most convincing biological interpretation of the genetic findings implicates altered synaptic function in autism spectrum disorder and schizophrenia. However, the mechanistic understanding is still incomplete. In line with their extensive clinical and epidemiological overlap, psychiatric disorders appear to exist on genetic continua and share a large degree of genetic risk with one another. This provides further support to the notion that current psychiatric diagnoses do not represent distinct pathogenic entities, which may inform ongoing attempts to reconceptualize psychiatric nosology. Psychiatric disorders also share genetic influences with a range of behavioral and somatic traits and diseases, including brain structures, cognitive function, immunological phenotypes and cardiovascular disease, suggesting shared genetic etiology of potential clinical importance. Current polygenic risk score tools, which predict individual genetic susceptibility to illness, do not yet provide clinically actionable information. However, their precision is likely to improve in the coming years, and they may eventually become part of clinical practice, stressing the need to educate clinicians and patients about their potential use and misuse. This review discusses key recent insights from psychiatric genetics and their possible clinical applications, and suggests future directions.     

Parental Authority, Future Autonomy, and Assessing Risks of Predictive Genetic Testing in Minors

The debate over the genetic testing of minors has developed into a major bioethical topic. Although several controversial questions remain unanswered, a degree of consensus has been reached regarding the policies on genetic testing of minors. Recently, several commentators have suggested that these policies are overly restrictive, too narrow in focus, and even in conflict with the limited empirical evidence that exists on this issue. We respond to these arguments in this paper, by first offering a clarification of three key concepts—autonomy of the minor, future autonomy, and parental authority—which must be disentangled. We then respond to the arguments by noting the uncertainty of the value of predictive genetic information, and by assessing the psychosocial risks still involved in genetic testing of minors, which are also largely unknown. We conclude that the current consensus position is justified at this stage, in light of the predictions of harm resulting from genetic testing of minors that have not been adequately proved to be unwarranted.     

Mental health benefits of omega-3 fatty acids may be mediated by improvements in cerebral vascular function

Since the pivotal role of long chain omega-3 (n-3) polyunsaturated fatty acids (PUFA) in brain structure and development became apparent in the 1970s, these lipids have been investigated in relation to a range of psychiatric disorders, with some positive and some conflicting evidence to support their use as a supplementary treatment for various symptoms. A number of mechanisms of action have been proposed to account for their potential benefits, largely based on their structural role in brain development and purported influences on central neurotransmission.Theories on the pathogenesis of mental health and psychiatric illness have traditionally focused on the role of neurotransmitters, although there is also ample evidence that psychiatric disorders are associated with impaired cerebral blood flow (CBF) or impairments in blood-brain barrier (BBB) function. Associations between cardiovascular and psychiatric pathologies are further indicative of a possible underlying vascular component to psychiatric illness. We hypothesise that treatment with vasoactive nutrients that can improve cerebral perfusion may help to improve a variety of mental disorders.In presenting our hypothesis, we provide an overview of cerebral vascular function, focusing specifically on the role of the endothelium in CBF and BBB integrity, and review evidence for associations between impaired CBF/endothelial function and psychiatric illness. Then, as an example of a potential treatment, we review the influence of n-3 PUFA on endothelial function, drawing on evidence of anti-inflammatory, anti-aggregatory and vasodilatory roles in blood flow and vascular permeability. We hypothesise that n-3 PUFA may act on the blood side of the BBB as well as on central neural pathways to influence cerebral functions. In the former case, they may act on endothelial cells to influence both vasodilation and selective permeability, thereby assisting in CBF and delivery of oxygen and glucose to brain tissue in response to requirements.     

Perturbateurs endocriniens et troubles du comportement

Prenatal environmental events that disturb neurodevelopment are suspected to increase the risk of psychiatric disorders. Estrogenic hormones such as diethylstilbestrol (DES) and environmental monomers like Bisphenol A (BPA) have the potential to disturb the development of the foetus and especially its brain. We reviewed the epidemiological studies investigating a possible association between prenatal DES or BPA exposure and risk of psychiatric disorders and discussed the hypothetical biological mechanisms linking this prenatal exposure with psychiatric disorders. The principal methodological issues that could represent confounding factors and may explain conflicting results are discussed. Interestingly, prenatal exposure to DES and BPA has been linked to epigenetic alterations associated with urogenital lesions observed in the exposed offspring, supporting the hypothesis that this environmental factor can indeed alter epigenetic regulations. Following the same line of thinking, these endocrine disruptors may modify the epigenetic mechanisms involved in neurodevelopment and, in turn, increase the occurrence of psychiatric disorders.     

非人灵长类动物模型睡眠研究在神经精神疾病的早期诊断和药效评价中的作用

清醒-睡眠的周期性调节需要众多单胺类神经递质(5-HT、NE、DA等)、乙酰胆碱等兴奋性神经递质以及GABA等抑制性神经递质的参与。这些递质系统的异常不仅会导致睡眠周期紊乱,还与一系列的精神性和神经退行性疾病相关。睡眠异常被认为是抑郁症、帕金森氏病等神经系统疾病发生的早期预警信号。相比起低等哺乳动物,非人灵长类动物的睡眠与人类的睡眠具有更好的可比性。近来,利用非人灵长类动物来建立神经精神疾病模型的研究已取得明显进展。在建模的同时监测动物的睡眠状况,有助于我们进一步了解睡眠在这些疾病早期诊断和发展过程中的作用,为疾病的早期诊断、治疗和药效评价提供更好的客观依据。     

Genetic tests obtainable through pharmacies: the good,the bad,and the ugly

Genomic medicine seeks to exploit an individual’s genomic information in the context of guiding the clinical decision-making process. In the post-genomic era, a range of novel molecular genetic testing methodologies have emerged, allowing the genetic testing industry to grow at a very rapid pace. As a consequence, a considerable number of different private diagnostic testing laboratories now provide a wide variety of genetic testing services, often employing a direct-to-consumer (DTC) business model to identify mutations underlying (or associated with) common Mendelian disorders, to individualize drug response, to attempt to determine an individual’s risk of a multitude of complex (multifactorial) diseases, or even to determine a person’s identity. Recently, we have noted a novel trend in the provision of private molecular genetic testing services, namely saliva and buccal swab collection kits (for deoxyribonucleic acid (DNA) isolation) being offered for sale over the counter by pharmacies. This situation is somewhat different from the standard DTC genetic testing model, since pharmacists are healthcare professionals who are supposedly qualified to give appropriate advice to their clients. There are, however, a number of issues to be addressed in relation to the marketing of DNA collection kits for genetic testing through pharmacies, namely a requirement for regulatory clearance, the comparative lack of appropriate genetics education of the healthcare professionals involved, and most importantly, the lack of awareness on the part of both the patients and the general public with respect to the potential benefits or otherwise of the various types of genetic test offered, which may result in confusion as to which test could be beneficial in their own particular case. We believe that some form of genetic counseling should ideally be integrated into, and made inseparable from, the genetic testing process, while pharmacists should be obliged to receive some basic training about the genetic tests that they offer for sale.     

Post‐GWAS in Psychiatric Genetics: A Developmental Perspective on the “Other” Next Steps

As psychiatric genetics enters an era where gene identification is finally yielding robust, replicable genetic associations and polygenic risk scores, it is important to consider next steps and delineate how that knowledge will be applied to ultimately ameliorate suffering associated with substance use and psychiatric disorders. Much of the post‐genome‐wide association study discussion has focused on the potential of genetic information to elucidate the underlying biology and use this information for the development of more effective pharmaceutical treatments. In this review we focus on additional areas of research that should follow gene identification. By taking genetic findings into longitudinal, developmental studies, we can map the pathways by which genetic risk manifests across development, elucidating the early behavioral manifestations of risk, and studying how various environments and interventions moderate that risk across developmental stages. The delineation of risk across development will advance our understanding of mechanism, sex differences and risk and resilience processes in different racial/ethnic groups. Here, we review how the extant twin study literature can be used to guide these efforts. Together, these new lines of research will enable us to develop more informed, tailored prevention and intervention efforts.     

Animal models of anxiety and their molecular dissection

Genetic approaches to psychiatric illness need appropriate animal models both for investigating how genetic variants give rise to behavioural disorder and for identifying genes that may be important in human conditions. Yet the relevance of many animal models to psychiatric illness is often not clear. Here I discuss how genetic approaches can be used to validate animal models of anxiety, an approach which is applicable to other animal models. One drawback of genetic validation is the difficulty inherent in identifying the molecular variants that influence the phenotype. I review genetic approaches that have the potential to overcome this problem.     

Premenstrual mood changes in affective disorders.

Mood changes during the premenstrual phase have been the focus of considerable research in recent years. Although there has been significant progress in the diagnosis and etiology of major affective disorders, the relation between these disorders and menstrual changes remains controversial. There have been contradictory reports and speculations on women''s susceptibility to psychiatric disorders during the premenstrual phase. We describe three patients with a history of mood swings associated with menstruation in whom major affective disorders developed, necessitating intensive psychiatric treatment or admission to hospital. Among women who manifest menstrual mood changes, manic-depressive illness may develop only in a subgroup with genetic predisposition. In such cases the possibility of postpartum mania or depression should be kept in mind in follow-up.     

Reconsideration of bipolar disorder as a developmental disorder: Importance of the time of onset

Bipolar disorder is a multifactorial psychiatric disorder with developmental and progressive neurophysiological alterations. This disorder is typically characterized by cyclical and recurrent episodes of mania and depression but is heterogeneous in its clinical presentation and outcome. Although the DSM-IV-TR criteria identify several features that are of phenomenological relevance, these are of less utility for defining homogeneous subgroups, for analyses of correlations with biomarkers or for directing focused medication strategies. We provide a comprehensive review of existing evidence regarding to age at onset in bipolar disorder. Eight admixture studies demonstrate three homogeneous subgroups of patients with bipolar disorder identified according to age at onset (early, intermediate and late age at onset), with two cutoff points, at 21 and 34 years. It is suggested that the early-onset subgroup has specific clinical features and outcomes different from those of the other subgroups. Early-onset subgroup may be considered a more suitable clinical phenotype for the identification of susceptibility genes with recent data demonstrating associations with genetic variants specifically in this subgroup. The use of age at onset as a specifier may also facilitate the identification of other biological markers for use in brain imaging, circadian, inflammatory and cognitive research. A key challenge is posed by the use of age at onset in treatment decision algorithms, although further research is required to increase the evidence-base. We discuss three potential benefits of specifying age at onset, namely: focused medication strategies, the targeted prevention of specific comorbid conditions and decreasing the duration of untreated illness. We argue that age at onset should be included as a specifier for bipolar disorders.     

Intervention, causal reasoning, and the neurobiology of mental disorders: Pharmacological drugs as experimental instruments

In psychiatry, pharmacological drugs play an important experimental role in attempts to identify the neurobiological causes of mental disorders. Besides being developed in applied contexts as potential treatments for patients with mental disorders, pharmacological drugs play a crucial role in research contexts as experimental instruments that facilitate the formulation and revision of neurobiological theories of psychopathology. This paper examines the various epistemic functions that pharmacological drugs serve in the discovery, refinement, testing, and elaboration of neurobiological theories of mental disorders. I articulate this thesis with reference to the history of antipsychotic drugs and the evolution of the dopamine hypothesis of schizophrenia in the second half of the twentieth century. I argue that interventions with psychiatric patients through the medium of antipsychotic drugs provide researchers with information and evidence about the neurobiological causes of schizophrenia. This analysis highlights the importance of pharmacological drugs as research tools in the generation of psychiatric knowledge and the dynamic relationship between practical and theoretical contexts in psychiatry.     

Genetic testing and genetic counseling among medicaid-enrolled children with autism spectrum disorder in 2001 and 2007

The rise in the prevalence of autism spectrum disorder (ASD) has resulted in increased efforts to understand the causes of this complex set of disorders that emerge early in childhood. Although research in this area is underway and yielding useful, but complex information about ASD, guidelines for the use of genetic testing and counseling among children with ASD conflict. The purpose of this study was to determine the frequency of use of genetic testing and counseling before the widespread implementation of clinical chromosomal microarray (CMA) to establish a baseline for the use of both services and to investigate potential disparities in the use of both services among children with ASD. We found that about two-thirds of children with ASD received genetic testing or counseling and the use of both services is increasing with time, even in the pre-CMA era. Being female and having a comorbid intellectual disability diagnosis both increased the likelihood of receiving genetic testing and genetic counseling. Initial discrepancies in the use of both services based on race/ethnicity suggest that troubling disparities observed in other services delivered to children with ASD and other mental health disorders persist in genetic testing and counseling as well. These results should incentivize further investigation of the impact of genetic testing and counseling on children with ASD and their families, and should drive efforts to explore and confront disparities in the delivery of these services, particularly with the advancing scientific research on this topic.     

Hyperactivity of CRH neuronal circuits as a target for therapeutic interventions in affective disorders

Increasing evidence suggests that the neuroendocrine changes seen in psychiatric patients, especially in those suffering from affective disorders, may be causally related to the psychopathology and course of these clinical conditions. The most robustly confirmed neuroendocrine finding among psychiatric patients with affective disorders is hyperactivity of the hypothalamic-pituitary-adrenocortical (HPA) system, resulting from hyperactive hypothalamic corticotropin-releasing hormone (CRH) neurons. A large body of preclinical and clinical evidence suggests that both genetic and environmental factors contribute to the development of these HPA system abnormalities. Further, normalization of HPA system regulation was shown to be a prerequisite for favorable treatment response and stable remission among depressives. Preclinical data based on animal models including selectively bred rat lines and mouse mutants support the notion that CRH neurons are hyperactive also in neuroanatomical regions that are involved in behavioral regulation but are located outside the neuroendocrine system. This raises the question of whether more direct interventions such as CRH receptor antagonists would open a new lead in the treatment of stress-related disorders such as depression, anxiety and sleep disorders. Recent clinical observations support this possibility.     

Sequencing of DISC1 pathway genes reveals increased burden of rare missense variants in schizophrenia patients from a northern Swedish population

In recent years, DISC1 has emerged as one of the most credible and best supported candidate genes for schizophrenia and related neuropsychiatric disorders. Furthermore, increasing evidence--both genetic and functional--indicates that many of its protein interaction partners are also involved in the development of these diseases. In this study, we applied a pooled sample 454 sequencing strategy, to explore the contribution of genetic variation in DISC1 and 10 of its interaction partners (ATF5, Grb2, FEZ1, LIS-1, PDE4B, NDE1, NDEL1, TRAF3IP1, YWHAE, and ZNF365) to schizophrenia susceptibility in an isolated northern Swedish population. Mutation burden analysis of the identified variants in a population of 486 SZ patients and 514 control individuals, revealed that non-synonymous rare variants with a MAF<0.01 were significantly more present in patients compared to controls (8.64% versus 4.7%, P?=?0.018), providing further evidence for the involvement of DISC1 and some of its interaction partners in psychiatric disorders. This increased burden of rare missense variants was even more striking in a subgroup of early onset patients (12.9% versus 4.7%, P?=?0.0004), highlighting the importance of studying subgroups of patients and identifying endophenotypes. Upon investigation of the potential functional effects associated with the identified missense variants, we found that ～90% of these variants reside in intrinsically disordered protein regions. The observed increase in mutation burden in patients provides further support for the role of the DISC1 pathway in schizophrenia. Furthermore, this study presents the first evidence supporting the involvement of mutations within intrinsically disordered protein regions in the pathogenesis of psychiatric disorders. As many important biological functions depend directly on the disordered state, alteration of this disorder in key pathways may represent an intriguing new disease mechanism for schizophrenia and related neuropsychiatric diseases. Further research into this unexplored domain will be required to elucidate the role of the identified variants in schizophrenia etiology.     

Molecular Genetic Testing in Endocrinology—A Practical Guide

ObjectiveTo discuss the factors to consider when evaluating patients with a suspected genetic endocrine disorder, so as to guide practicing endocrinologists through the process of genetic testing and result interpretation.MethodsThe author’s experience and review of appropriate literature have been used to give a personal perspective on the role of genetic testing in hereditary endocrine disorders.ResultsRecent advances in our understanding of genetics and genomics have uncovered that they have a far more important role in the pathogenesis of endocrine disease than previously appreciated. Not only are we expanding our understanding of rare mendelian disorders such as multiple endocrine neoplasia type 1 and 2, but we are also beginning to understand the clinical significance of genetic factors in the pathogenesis of common disorders such as obesity and dyslipidemia.ConclusionsIt can be difficult to appreciate the clinical significance and utility of genetic testing that is currently available, and the interpretation of genetic test results can be challenging. Decisions on whether genetic testing is needed should be made on a case-by-case basis, with the endocrinologist and geneticist working together from the outset. (Endocr Pract. 2012;18:85-89)     

Opinion: predictive testing for Huntington disease in childhood: challenges and implications.

Predictive testing for HD strongly highlights the need for autonomy and the need for each individual to decide about his or her willingness-or unwillingness-to obtain genetic information predictive of the future outcome. In respect of this principle, testing for minors should not be offered at the request of a third party, and prenatal testing which would result in the birth of a child at increased risk for HD should, where possible, be avoided. If we accede to the wishes of the parents for their children to be tested, we will have broken the primary principles of confidentiality, privacy, and individual justice that are owed to those children. This could be the thin edge of a wedge which could result in adoption agencies, educational institutions, insurance companies, and other third parties demanding genetic testing for another individual. Despite years of careful planning, predictive testing for HD is turning out to be more complex and challenging than ever expected. We need a great deal of care and concern in developing our response to this challenge. Careful long-term assessment and documentation of the impact of such testing is needed, so that the appropriate guidelines can be developed, guidelines which both protect families with HD and at the same time give individuals the opportunity to participate in predictive testing programs.     

Association of polyaminergic loci with anxiety, mood disorders, and attempted suicide

Background

The polyamine system has been implicated in a number of psychiatric conditions, which display both alterations in polyamine levels and altered expression of genes related to polyamine metabolism. Studies have identified associations between genetic variants in spermidine/spermine N1-acetyltransferase (SAT1) and both anxiety and suicide, and several polymorphisms appear to play important roles in determining gene expression.

Methodology/Principal Findings

We genotyped 63 polymorphisms, spread across four polyaminergic genes (SAT1, spermine synthase (SMS), spermine oxidase (SMOX), and ornithine aminotransferase like-1 (OATL1)), in 1255 French-Canadian individuals who have been followed longitudinally for 22 years. We assessed univariate associations with anxiety, mood disorders, and attempted suicide, as assessed during early adulthood. We also investigated the involvement of gene-environment interactions in terms of childhood abuse, and assessed internalizing and externalizing symptoms as endophenotypes mediating these interactions. Overall, each gene was associated with at least one main outcome: anxiety (SAT1, SMS), mood disorders (SAT1, SMOX), and suicide attempts (SAT1, OATL1). Several SAT1 polymorphisms displayed disease-specific risk alleles, and polymorphisms in this gene were involved in gene-gene interactions with SMS to confer risk for anxiety disorders, as well as gene-environment interactions between childhood physical abuse and mood disorders. Externalizing behaviors demonstrated significant mediation with regards to the association between OATL1 and attempted suicide, however there was no evidence that externalizing or internalizing behaviors were appropriate endophenotypes to explain the associations with mood or anxiety disorders. Finally, childhood sexual abuse did not demonstrate mediating influences on any of our outcomes.

Conclusions/Significance

These results demonstrate that genetic variants in polyaminergic genes are associated with psychiatric conditions, each of which involves a set of separate and distinct risk alleles. As several of these polymorphisms are associated with gene expression, these findings may provide mechanisms to explain the alterations in polyamine metabolism which have been observed in psychiatric disorders.