Evolution of the expression and regulation of the nuclear hormone receptor ERR gene family in the chordate lineage.

The Estrogen Related Receptor (ERR) nuclear hormone receptor genes have a wide diversity of roles in vertebrate development. In embryos, ERR genes are expressed in several tissues, including the central and peripheral nervous systems. Here we seek to establish the evolutionary history of chordate ERR genes, their expression and their regulation. We examine ERR expression in mollusc, amphioxus and sea squirt embryos, finding the single ERR orthologue is expressed in the nervous system in all three, with muscle expression also found in the two chordates. We show that most jawed vertebrates and lampreys have four ERR paralogues, and that vertebrate ERR genes were ancestrally linked to Estrogen Receptor genes. One of the lamprey paralogues shares conserved expression domains with jawed vertebrate ERRγ in the embryonic vestibuloacoustic ganglion, eye, brain and spinal cord. Hypothesising that conserved expression derives from conserved regulation, we identify a suite of pan-vertebrate conserved non-coding sequences in ERR introns. We use transgenesis in lamprey and chicken embryos to show that these sequences are regulatory and drive reporter gene expression in the nervous system. Our data suggest an ancient association between ERR and the nervous system, including expression in cells associated with photosensation and mechanosensation. This includes the origin in the vertebrate common ancestor of a suite of regulatory elements in the 3' introns that drove nervous system expression and have been conserved from this point onwards.

Transgenes of genetically modified animals detected non-invasively via environmental DNA.

We demonstrate that simple, non-invasive environmental DNA (eDNA) methods can detect transgenes of genetically modified (GM) animals from terrestrial and aquatic sources in invertebrate and vertebrate systems. We detected transgenic fragments between 82-234 bp through targeted PCR amplification of environmental DNA extracted from food media of GM fruit flies (Drosophila melanogaster), feces, urine, and saliva of GM laboratory mice (Mus musculus), and aquarium water of GM tetra fish (Gymnocorymbus ternetzi). With rapidly growing accessibility of genome-editing technologies such as CRISPR, the prevalence and diversity of GM animals will increase dramatically. GM animals have already been released into the wild with more releases planned in the future. eDNA methods have the potential to address the critical need for sensitive, accurate, and cost-effective detection and monitoring of GM animals and their transgenes in nature.

Unemployment among patients with newly diagnosed first-episode psychosis: prevalence and clinical correlates in a U.S. sample.

PURPOSE: Although it is well established that people with schizophrenia have markedly high rates of unemployment, less is known about the prevalence and clinical correlates of unemployment in patients newly diagnosed with first-episode psychosis. This analysis documented the prevalence of unemployment and examined previously reported clinical correlates of unemployment in patients with first-episode psychosis hospitalized in an urban, public-sector setting in the southeastern US. METHODS: Participants (n = 181) were assessed as part of an overarching study of first-episode psychosis using a variety of standardized research instruments. The rate of unemployment was compared to that documented in the general population according to US census data. Bivariate tests of associations between employment status and a number of variables of interest were followed by a multiple logistic regression model based on a previous study from Dublin, Ireland. RESULTS: Some 65.0% of first-episode patients were unemployed in the month prior to hospital admission, which is substantially higher than the rate of unemployment during the same period in the two counties in which recruitment took place. In bivariate tests, unemployment was associated with younger age, fewer years of educational attainment, lower global functioning scores, and more severe negative symptoms. In the logistic regression model, only age and global functioning were independently significant correlates. CONCLUSIONS: The remarkably high rate of unemployment in this young, first-episode sample, and the evidence of associations between unemployment, greater symptomatology, and poorer functioning, argue for further research and development on supported employment programs for such patients.

An exploration of perceptions of possible depression prevention services for caregivers of elderly or chronically ill adults in rural Georgia.

Caregiving for elderly or chronically ill adults can be stressful, contributing to a high rate of depression in caregivers. Rural caregivers are at particularly high risk due to reduced access to mental health care services. This study explored the acceptability among rural caregivers of introducing a program to prevent or alleviate depression. Focus groups with caregivers and community members were conducted in four rural counties of Georgia. Caregivers reported high levels of stress and depression and recommended the following interventions: support groups, respite care, a centralized source of information, training for caregivers and other community members, financial support, and a telephone hotline. There were more commonalities than differences across the locations, but some programmatic preferences and acceptability varied.

Life and treatment goals of individuals hospitalized for first-episode nonaffective psychosis.

First-episode psychosis typically emerges during late adolescence or young adulthood, interrupting achievement of crucial educational, occupational, and social milestones. Recovery-oriented approaches to treatment may be particularly applicable to this critical phase of the illness, but more research is needed on the life and treatment goals of individuals at this stage. Open-ended questions were used to elicit life and treatment goals from a sample of 100 people hospitalized for first-episode psychosis in an urban, public-sector setting in the southeastern United States. Employment, education, relationships, housing, health, and transportation were the most frequently stated life goals. When asked about treatment goals, participants' responses included wanting medication management, reducing troubling symptoms, a desire to simply be well, engaging in counseling, and attending to their physical health. In response to queries about specific services, most indicated a desire for both vocational and educational services, as well as assistance with symptoms and drug abuse. These findings are interpreted and discussed in light of emerging or recently advanced treatment paradigms-recovery and empowerment, shared decision-making, community and social reintegration, and phase-specific psychosocial treatment. Integration of these paradigms would likely promote recovery-oriented tailoring of early psychosocial interventions, such as supported employment and supported education, for first-episode psychosis.

Clinical correlates of maltreatment and traumatic experiences in childhood and adolescence among predominantly African American, socially disadvantaged, hospitalized, first-episode psychosis patients.

Associations among maltreatment and traumatic experiences in childhood and adolescence, later substance use, and subsequent mental health outcomes for individuals with schizophrenia-spectrum disorders have been initially explored in previous studies; however, research on these factors in socially disadvantaged patients with first-episode psychosis is unavailable. This exploratory, correlational analysis examined associations between maltreatment and trauma-related variables (e.g., traumatic experiences, parental harsh discipline, violence exposure) and: social variables (years of education attained and extent of Axis IV psychosocial problems at initial hospitalization), substance abuse (age at initiation of alcohol and cannabis use, as well as estimates of lifetime intake of both), and positive and negative symptom severity. Rates of childhood abuse and traumatic events were remarkably high in the sample. Years of educational attainment and number of Axis IV psychosocial problems were substantially correlated with several domains of childhood abuse/traumatic events. Age at initiation of alcohol and cannabis use, and lifetime alcohol and cannabis intake, were correlated with a number of trauma domains. Whereas positive symptom severity was correlated with four of the trauma variables, negative symptom severity was correlated only with prior emotional neglect. These results provide insights into the relations among childhood traumatic events, substance use, and clinical features of first-episode psychosis, creating hypotheses for future research.

Prevalence and psychosocial correlates of prior incarcerations in an urban, predominantly African-American sample of hospitalized patients with first-episode psychosis.

High rates of incarceration and criminal justice system recidivism among individuals with serious mental illnesses have long been topics of concern, but few studies have examined rates of prior incarceration at the point of first treatment contact. In a sample of 109 urban, low-income, predominantly African-American patients hospitalized for first-episode psychosis, 57.8 percent reported a history of incarceration. Among those who reported having ever been incarcerated, 58.1 percent had more than one past incarceration, and the mean number of incarcerations was 2.9 ± 3.4. Patients with a history of incarceration had completed fewer years of education, had poorer late-adolescence premorbid academic functioning, reported an earlier age at initiation of cannabis use, and were more likely to have cannabis and alcohol dependence or abuse. Incarceration was also associated with a greater number of psychosocial problems and more severe general psychopathology symptoms. These findings of excessively high rates of past incarceration among urban, predominantly African-American, first-episode psychosis patients, along with the associations between past incarceration and diverse adverse psychosocial and clinical characteristics, serve as a call to action for researchers in early psychosis, program developers, policy-makers, and clinical and forensic psychiatrists.

Overview and initial validation of two detailed, multidimensional, retrospective measures of substance use: the Lifetime Substance Use Recall (LSUR) and Longitudinal Substance Use Recall for 12 Weeks (LSUR-12) Instruments.

Research on comorbidities between substance use disorders and serious mental illnesses would be facilitated by new methods for collecting comprehensive data on substance use, including data on onset, progression, frequency, amounts, and consequential behaviors. Given substantial limitations of available instruments, and a nearly complete absence of methodologies that allow derivation of continuous measures that estimate dose or cumulative exposure, this report describes the development and initial validation of two interviewer-administered, multidimensional measures of substance use, the Lifetime Substance Use Recall (LSUR) and Longitudinal Substance Use Recall for 12 Weeks (LSUR-12) Instruments. Participants (n=60) in an ongoing study of first-episode psychosis were evaluated with the LSUR, LSUR-12, and a number of other concurrent measures pertaining to substance use, substance use disorder diagnoses, select demographic features, and two personality traits. Specific a priori hypothesis tests were selected to demonstrate validity, relying on effect sizes to estimate strengths of association, considering small-to-medium correlations (e.g., ρ) as |.20-.50| and medium-to-large effect sizes as >|.50|. Numerous associations were observed between key nicotine-, alcohol-, and cannabis-related variables from the LSUR and LSUR-12 and scores from other concurrently administered measures. These findings provide a thorough initial validation of scores obtained with the new multidimensional instruments. Although validity of the two new measures of lifetime and past 12-week substance use was demonstrated, empirical data on inter-rater and test-retest reliability are needed. Careful development, and demonstration of psychometric properties, of these and related instruments may advance the fields of addiction and comorbidity research.

Pre-illness cannabis use and the early course of nonaffective psychotic disorders: associations with premorbid functioning, the prodrome, and mode of onset of psychosis.

INTRODUCTION: Limited research indicates that pre-illness cannabis use may result in an earlier age at onset of psychosis, though little is known about the influence of prior cannabis use on the premorbid and prodromal phases. This study examined the effects of prior or concurrent cannabis (as well as nicotine and alcohol) use on: (1) early adolescent (12-15 years) premorbid functioning, (2) late adolescent (16-18 years) premorbid functioning, (3) two features of the prodrome, and (4) mode of onset of psychosis. METHODS: Participants included 109 well-characterized first-episode patients hospitalized in public-sector settings. Assessments included ages at initiation of first, weekly, and daily use of substances, the Premorbid Adjustment Scale, the Symptom Onset in Schizophrenia inventory, and a consensus-based best estimate of mode of onset. RESULTS: Participants having used cannabis at ≤15 years had better early adolescence social functioning than those who had not used cannabis (p=0.02). Conversely, those who had used cannabis at ≤18 years had poorer late adolescence academic functioning (p<0.001). Participants having used cannabis before onset of psychotic symptoms did not differ from those who had not in terms of having had an identifiable prodrome or the number of prodromal symptoms experienced. Whereas 42% of those having used cannabis daily had an acute mode of onset of psychosis, only 20% of those without prior daily cannabis use had an acute onset (p=0.04). CONCLUSIONS: Findings suggest that cannabis use is associated with premorbid social and academic functioning and mode of onset. Further research is warranted to elucidate the complex associations between cannabis use and diverse early-course features.

Predictors of the discharge dosage of an atypical antipsychotic agent among hospitalized, treatment-naive, first-episode psychosis patients in naturalistic, public-sector settings.

OBJECTIVE: Little is known about determinants of second-generation antipsychotic dosages during initial hospitalization of first-episode psychosis. This study examined potential predictors of dosage of an atypical antipsychotic agent, risperidone, at hospital discharge after initial evaluation and treatment of first-episode nonaffective psychosis in 3 naturalistic, public-sector treatment settings. METHODS: The number of psychotropic agents prescribed and discharge antipsychotic dosage were abstracted from the medical record. Demographic and extensive clinical characteristics were assessed through a clinical research study conducted at the 3 sites. One-way analyses of variance, trend tests using specific linear combinations of estimates, and χ² tests assessed for associations between atypical antipsychotic dosage and 5 hypothesized predictors, as well as 12 exploratory variables. RESULTS: Among 155 hospitalized first-episode patients, 121 (78.1%) were discharged on risperidone, and subsequent analyses focused on that subset. The mean risperidone dosage among those 121 patients was 4.26 mg; 31 received 1 to 2 mg, 45 received 3 to 4 mg, 37 received 5 to 6 mg, and 8 received more than 6 mg. Analyses suggested that older age at hospitalization, the number of psychotropic agents prescribed, excited symptoms, and premorbid social functioning may be predictors of the discharge dosage. CONCLUSIONS: Although several factors emerged, in general, predictors of discharge dosages of second-generation agents, here exemplified by risperidone, in real-world practice settings remain to be clarified. Given the importance of antipsychotic initiation during first hospitalization, future research should test an even broader array of potential predictors.

Health services determinants of the duration of untreated psychosis among African-American first-episode patients.

OBJECTIVE: The duration of untreated psychosis is associated with poor outcomes in multiple domains in the early course of nonaffective psychotic disorders, although relatively little is known about determinants of this critical period, particularly health services-level determinants. This study examined three hypothesized predictors of duration of untreated psychosis (lack of insurance, financial problems, and broader barriers) among urban, socioeconomically disadvantaged African Americans, while controlling for the effects of three patient-level predictors (mode of onset of psychosis, living with family versus alone or with others before hospitalization, and living above versus below the federally defined poverty level). METHODS: Analyses included data from 42 patient-family member dyads from a larger sample of 109 patients with a first episode of nonaffective psychosis. The duration of untreated psychosis and all other variables were measured in a rigorous, standardized fashion in a study designed specifically to examine determinants of treatment delay. Survival analyses and Cox regression assessed the effects of the independent predictors on time from onset of psychosis to hospital admission for initial evaluation and treatment. RESULTS: The median duration of untreated psychosis was 24.5 weeks. When the analyses controlled for the three patient-level covariates, patients without health insurance, with financial problems, or with barriers to seeking help had a significantly longer duration of untreated psychosis. CONCLUSIONS: Health services-related factors, such as lack of insurance, are predictive of longer treatment delay. Efforts to eliminate uninsurance and underinsurance, as well as minimize barriers to treatment, would be beneficial for improving the prognosis of young patients with emerging nonaffective psychotic disorders.

Association of pre-onset cannabis, alcohol, and tobacco use with age at onset of prodrome and age at onset of psychosis in first-episode patients.

OBJECTIVE: Several reports suggest that cannabis use is associated with an earlier age at onset of psychosis, although not all studies have operationalized cannabis use as occurring prior to onset of symptoms. This study addressed whether pre-onset cannabis use, alcohol use, and tobacco use are associated with an earlier age at onset of prodromal and psychotic symptoms. Effects of the progression of frequency of use were examined through time-dependent covariates in survival analyses. METHOD: First-episode patients (N=109) hospitalized in three public-sector inpatient psychiatric units underwent in-depth cross-sectional retrospective assessments. Prior substance use and ages at onset of prodromal and psychotic symptoms were determined by standardized methods, and analyses were conducted using Cox regression modeling. RESULTS: Whereas classifying participants according to maximum frequency of use prior to onset (none, ever, weekly, or daily) revealed no significant effects of cannabis or tobacco use on risk of onset, analysis of change in frequency of use prior to onset indicated that progression to daily cannabis and tobacco use was associated with an increased risk of onset of psychotic symptoms. Similar or even stronger effects were observed when onset of illness or prodromal symptoms was the outcome. A gender-by-daily-cannabis-use interaction was observed; progression to daily use resulted in a much larger increased relative risk of onset of psychosis in females than in males. CONCLUSIONS: Pre-onset cannabis use may hasten the onset of psychotic as well as prodromal symptoms. Age at onset is a key prognostic factor in schizophrenia, and discovering modifiable predictors of age at onset is crucial.

EARLY DETECTION AND INTERVENTION FOR PSYCHOSIS: PERSPECTIVES FROM NORTH AMERICA.

Clinicians and researchers in Canada and the United States have established a number of early intervention programs and research sites on the early course of psychosis and the prodromal period that commonly precedes psychotic disorders. In Canada, early detection and treatment programs for psychosis have been established in many areas of the country, and typically serve specific catchment areas. Canadian research on early psychosis is often built on to these clinical sites, and covers a broad array of topics including interventions during the prodromal stage of the illness, treatment-seeking behaviors, and development of optimal pharmacological and psychosocial treatment approaches for early psychosis. In the United States, clinical programs for early intervention in psychosis are often located at academic programs with ongoing research on the early course of psychotic disorders. Researchers from sites across the United States offer a plethora of information, including neuroimaging studies, research on treatment response, and the development of standardized rating scales and research instruments. Researchers from sites in both countries have formed a consortium to launch the North American Prodrome Longitudinal Study, a multi-site collaboration to gain a better understanding of the prodromal period of the illness and prediction of conversion from the prodrome to psychosis.