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The genetic architecture of psychiatric disorders is characterized by a large number of small-effect variants located primarily in non-coding regions, suggesting that the underlying causal effects may influence disease risk by modulating gene expression. We provide comprehensive analyses using transcriptome data from an unprecedented collection of tissues to gain pathophysiological insights into the role of the brain, neuroendocrine factors (adrenal gland) and gastrointestinal systems (colon) in psychiatric disorders. In each tissue, we perform PrediXcan analysis and identify trait-associated genes for schizophrenia (n associations = 499; n unique genes = 275), bipolar disorder (n associations = 17; n unique genes = 13), attention deficit hyperactivity disorder (n associations = 19; n unique genes = 12) and broad depression (n associations = 41; n unique genes = 31). Importantly, both PrediXcan and summary-data-based Mendelian randomization/heterogeneity in dependent instruments analyses suggest potentially causal genes in non-brain tissues, showing the utility of these tissues for mapping psychiatric disease genetic predisposition. Our analyses further highlight the importance of joint tissue approaches as 76% of the genes were detected only in difficult-to-acquire tissues.
For more than a century, research on psychopathology has focused on categorical diagnoses. Although this work has produced major discoveries, growing evidence points to the superiority of a dimensional approach to the science of mental illness. Here we outline one such dimensional system-the Hierarchical Taxonomy of Psychopathology (HiTOP)-that is based on empirical patterns of co-occurrence among psychological symptoms. We highlight key ways in which this framework can advance mental-health research, and we provide some heuristics for using HiTOP to test theories of psychopathology. We then review emerging evidence that supports the value of a hierarchical, dimensional model of mental illness across diverse research areas in psychological science. These new data suggest that the HiTOP system has the potential to accelerate and improve research on mental-health problems as well as efforts to more effectively assess, prevent, and treat mental illness.
Hypophosphatasia (HPP) typically manifests with fractures, tooth loss, and muscle pain. Although mental health diagnoses and neurological symptoms have not been previously well documented in HPP, they occur commonly. The recognition of non-traditional symptoms may improve patient satisfaction, preempt costly evaluation and misdiagnosis, and lead to further treatment options.
INTRODUCTION - Hypophosphatasia (HPP) is an inborn error of metabolism due to deficiency of tissue non-specific alkaline phosphatase (TNSALP). It is traditionally characterized by rickets in children and osteomalacia in adults, along with fractures, tooth loss, and muscle pain. Neurological symptoms and mental health diagnoses have not been widely reported, and we therefore report their prevalence in a cohort of patients with HPP.
METHODS - A retrospective chart review was performed on a series of 82 HPP patients. Patient charts were reviewed to identify the possible presence and onset of 13 common neurological symptoms.
RESULTS - Median age was 36 years (2 to 79). Seventeen had adult onset HPP (> 18 years) and 65 had pediatric onset HPP (< 18 years). Median time from symptom onset to HPP diagnosis was 8 years (0 to 67). Seventy-four percent had a family history of bone disease, while 17% had a family history of neurologic disease. Bone problems occurred in 89%, dental problems in 77%, and muscle problems in 66%. Fatigue occurred in 66%, headache in 61%, sleep disturbance in 51%, gait change in 44%, vertigo in 43%, depression in 39%, anxiety in 35%, neuropathy in 35%, and hearing loss in 33%.
CONCLUSIONS - The extra-skeletal manifestations of HPP, specifically neurological symptoms, have not been previously well documented. However, mental health diagnoses and neurological symptoms such as headache and sleep disturbance occur commonly in patients with HPP. The recognition of non-traditional symptoms in HPP may improve patient satisfaction, preempt costly evaluation and misdiagnosis, and may lead to further treatment options.
The majority of surviving infants with surgical necrotizing enterocolitis (NEC) will have some degree of neurodevelopmental impairment. The impact of specific medial and surgical treatments for infants with severe NEC remains largely unknown but is being actively investigated. It is incumbent upon all providers caring for these infants to continue to focus on long term neurodevelopmental outcomes and to develop more widespread methods of neurodevelopmental assessment.
Copyright © 2018 Elsevier Inc. All rights reserved.
There is evidence that models of psychopathology specifying a general factor and specific second-order factors fit better than competing structural models. Nonetheless, additional tests are needed to examine the generality and boundaries of the general factor model. In a selected second wave of a cohort study, first-order dimensions of psychopathology symptoms in 499 23- to 31-year-old twins were analyzed. Using confirmatory factor analysis, a bifactor model specifying a general factor and specific internalizing and externalizing factors fit better than competing models. Factor loadings in this model were sex invariant despite greater variances in the specific internalizing factor among females and greater variances in the general and specific externalizing factors among males. The bifactor structure was robust to the exclusion of any single first-order dimension of psychopathology. Furthermore, the results were essentially unchanged when all overlapping symptoms that define multiple disorders were excluded from symptom dimensions. Furthermore, the best-fitting bifactor model also emerged in exploratory structural equation modeling with freely estimated cross-loadings. The general factor of psychopathology was robust across variations in measurement and analysis.
Copyright © 2017 John Wiley & Sons, Ltd.
Recent genetic analyses have provided evidence that clinical commonalities associated with different psychiatric diagnoses often have shared mechanistic underpinnings. The development of animal models expressing functional genetic variation attributed to multiple disorders offers a salient opportunity to capture molecular, circuit and behavioral alterations underlying this hypothesis. In keeping with studies suggesting dopaminergic contributions to attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BPD) and autism spectrum disorder (ASD), subjects with these diagnoses have been found to express a rare, functional coding substitution in the dopamine (DA) transporter (DAT), Ala559Val. We developed DAT Val559 knock-in mice as a construct valid model of dopaminergic alterations that drive multiple clinical phenotypes, and here evaluate the impact of lifelong expression of the variant on impulsivity and motivation utilizing the 5- choice serial reaction time task (5-CSRTT) and Go/NoGo as well as tests of time estimation (peak interval analysis), reward salience (sucrose preference), and motivation (progressive ratio test). Our findings indicate that the DAT Val559 variant induces impulsivity behaviors that are dependent upon the reward context, with increased impulsive action observed when mice are required to delay responding for a reward, whereas mice are able to withhold responding if there is a probability of reward for a correct rejection. Utilizing peak interval and progressive ratio tests, we provide evidence that impulsivity is likely driven by an enhanced motivational phenotype that also may drive faster task acquisition in operant tasks. These data provide critical validation that DAT, and more generally, DA signaling perturbations can drive impulsivity that can manifest in specific contexts and not others, and may rely on motivational alterations, which may also drive increased maladaptive reward seeking.
Copyright © 2017 Elsevier B.V. All rights reserved.
In this meta-analytic and narrative review, we examine several overarching issues related to the study of coping, emotion regulation, and internalizing and externalizing symptoms of psychopathology in childhood and adolescence, including the conceptualization and measurement of these constructs. We report a quantitative meta-analysis of 212 studies (N = 80,850 participants) that measured the associations between coping and emotion regulation with symptoms of internalizing and externalizing psychopathology. Within the meta-analysis we address the association of broad domains of coping and emotion regulation (e.g., total coping, emotion regulation), intermediate factors of coping and emotion regulation (e.g., primary control coping, secondary control coping), and specific coping and emotion regulation strategies (e.g., emotional expression, cognitive reappraisal) with internalizing and externalizing symptoms. For cross-sectional studies, which made up the majority of studies included, we examine 3 potential moderators: age, measure quality, and single versus multiple informants. Finally, we separately consider findings from longitudinal studies as these provide stronger tests of the effects. After accounting for publication bias, findings indicate that the broad domain of emotion regulation and adaptive coping and the factors of primary control coping and secondary control coping are related to lower levels of symptoms of psychopathology. Further, the domain of maladaptive coping, the factor of disengagement coping, and the strategies of emotional suppression, avoidance, and denial are related to higher levels of symptoms of psychopathology. Finally, we offer a critique of the current state of the field and outline an agenda for future research. (PsycINFO Database Record
(c) 2017 APA, all rights reserved).
Abnormal reward processing is a prominent transdiagnostic feature of psychopathology. The present review provides a framework for considering the different aspects of reward processing and their assessment, and highlights recent insights from the field of neuroeconomics that may aid in understanding these processes. Although altered reward processing in psychopathology has often been treated as a general hypo- or hyperresponsivity to reward, increasing data indicate that a comprehensive understanding of reward dysfunction requires characterization within more specific reward-processing domains, including subjective valuation, discounting, hedonics, reward anticipation and facilitation, and reinforcement learning. As such, more nuanced models of the nature of these abnormalities are needed. We describe several processing abnormalities capable of producing the types of selective alterations in reward-related behavior observed in different forms of psychopathology, including (mal)adaptive scaling and anchoring, dysfunctional weighting of reward and cost variables, competition between valuation systems, and reward prediction error signaling.
Cholesterol metabolism is vital for brain function. Previous work in cultured cells has shown that a number of psychotropic drugs inhibit the activity of 7-dehydrocholesterol reductase (DHCR7), an enzyme that catalyzes the final steps in cholesterol biosynthesis. This leads to the accumulation of 7-dehydrocholesterol (7DHC), a molecule that gives rise to oxysterols, vitamin D, and atypical neurosteroids. We examined levels of cholesterol and the cholesterol precursors desmosterol, lanosterol, 7DHC and its isomer 8-dehydrocholesterol (8DHC), in blood samples of 123 psychiatric patients on various antipsychotic and antidepressant drugs, and 85 healthy controls, to see if the observations in cell lines hold true for patients as well. Three drugs, aripiprazole, haloperidol and trazodone increased circulating 7DHC and 8DHC levels, while five other drugs, clozapine, escitalopram/citalopram, lamotrigine, olanzapine, and risperidone, did not. Studies in rat brain verified that haloperidol dose-dependently increased 7DHC and 8DHC levels, while clozapine had no effect. We conclude that further studies should investigate the role of 7DHC and 8DHC metabolites, such as oxysterols, vitamin D, and atypical neurosteroids, in the deleterious and therapeutic effects of psychotropic drugs. Finally, we recommend that drugs that increase 7DHC levels should not be prescribed during pregnancy, as children born with DHCR7 deficiency have multiple congenital malformations.
Copyright © 2017 Elsevier B.V. All rights reserved.
We propose a taxonomy of psychopathology based on patterns of shared causal influences identified in a review of multivariate behavior genetic studies that distinguish genetic and environmental influences that are either common to multiple dimensions of psychopathology or unique to each dimension. At the phenotypic level, first-order dimensions are defined by correlations among symptoms; correlations among first-order dimensions similarly define higher-order domains (e.g., internalizing or externalizing psychopathology). We hypothesize that the robust phenotypic correlations among first-order dimensions reflect a . Some nonspecific etiologic factors increase risk for all first-order dimensions of psychopathology to varying degrees through a general factor of psychopathology. Other nonspecific etiologic factors increase risk only for all first-order dimensions within a more specific higher-order domain. Furthermore, each first-order dimension has its own unique causal influences. Genetic and environmental influences common to family members tend to be nonspecific, whereas environmental influences unique to each individual are more dimension-specific. We posit that these causal influences on psychopathology are moderated by sex and developmental processes. This causal taxonomy also provides a novel framework for understanding the of each first-order dimension: Different persons exhibiting similar symptoms may be influenced by different combinations of etiologic influences from each of the 3 levels of the etiologic hierarchy. Furthermore, we relate the proposed causal taxonomy to transdimensional psychobiological processes, which also impact the heterogeneity of each psychopathology dimension. This causal taxonomy implies the need for changes in strategies for studying the etiology, psychobiology, prevention, and treatment of psychopathology. (PsycINFO Database Record
(c) 2017 APA, all rights reserved).